DNA repair and mutagenesis:
Gespeichert in:
| Vorheriger Titel: | Friedberg, Errol C. DNA repair and mutagenesis |
|---|---|
| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Washington, DC
ASM Press
2006
|
| Ausgabe: | 2. ed. |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XXVII, 1118 S. Ill., graph. Darst. |
| ISBN: | 1555813194 |
Internformat
MARC
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| 245 | 1 | 0 | |a DNA repair and mutagenesis |c Errol C. Friedberg ... |
| 250 | |a 2. ed. | ||
| 264 | 1 | |a Washington, DC |b ASM Press |c 2006 | |
| 300 | |a XXVII, 1118 S. |b Ill., graph. Darst. | ||
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| 650 | 4 | |a ADN - Réparation | |
| 650 | 7 | |a DNA |2 gtt | |
| 650 | 7 | |a Mutagenesis |2 gtt | |
| 650 | 4 | |a Mutagenèse | |
| 650 | 4 | |a DNA repair | |
| 650 | 4 | |a Mutagenesis | |
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| 700 | 1 | |a Friedberg, Errol C. |e Sonstige |4 oth | |
| 780 | 0 | 0 | |i 1. Auflage |a Friedberg, Errol C. |t DNA repair and mutagenesis |
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Datensatz im Suchindex
| _version_ | 1804135139777708032 |
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| adam_text | Contents
Preface xxv
Abbreviations xxix
PART 1
Sources and Consequences of DNA Damage 1
1 I Introduction: Biological Responses to DNA Damage 3
I Historical Reflections 3
The Problem of Constant Genomic Insult 4
Biological Responses to DNA Damage 4
DNA Repair 4
DNA Damage Tolerance and Mutagenesis 5
Other Responses to DNA Damage 6
Disease States Associated with Defective Responses to DNA Damage 6
2 I DNA Damage 9
I Endogenous DNA Damage 9
Spontaneous Alterations in DNA Base Chemistry 9
Mismatches Created by DNA Replication Errors 24
Environmental DNA Damage 25
DNA Damage by Radiation 25
Chemical Agents That Damage DNA 35
DNA Damage and Chromatin Structure 48
UV Photoproduct Formation Is Influenced by Chromatin Structure1 and Binding of Oilier
Proteins 48
Chromosomal Structure and Bound Proteins Can Protect against DNA Damage in
Bacteria 49
Detection of DNA Damage by Proteins 50
Structural Information Is Encoded in DNA 50
Binding to Single Stranded DNA 54
Locating Sites of DNA Damage 55
Summary and Conclusions 57
vii
3 Introduction to Mutagenesis 71
Mutations and Mutants: Some Definitions 71
Point Mutations and Other Classes of Mutations 73
Base Substitution Mutations 73
Mutations Resulting from the Addition or Deletion of Small Numbers of Base Pairs 74
Systems Used To Detect and Analyze Mutations 75
Early Systems for the Analysis of Mutagenesis 75
The Ames Salmonella Test: a Widely Used Reversion System 76
E. coli Lad: an Example of a Forward Mutational System 77
Other Examples of Forward Mutational Systems 78
Special Systems To Detect Frameshift or Deletion Mutations 78
Analysis of Mutagenesis in Mammalian Cells 79
Use of Site Specific Adducts 85
Replication Fidelity and DNA Polymerase Structure 86
Templated Information in DNA 86
Energetics of Base Pairing 87
Geometric Selection of Nucleotides during DNA Synthesis 87
A Two Metal Ion Mechanism for DNA Synthesis 90
Open and Closed Conformations of DNA Polymerases 92
Importance of Base Pairing Geometry versus Hydrogen Bonds 92
Selection against Ribonucleotides 93
Proofreading during DNA Synthesis 93
Lesion Bypass by Error Prone DNA Polymerases 95
Conclusions about Replicative Fidelity 98
Mechanisms Contributing to Spontaneous Mutagenesis 98
Base Substitution Mutations Resulting from Misincorporation during DNA Synthesis 98
Mutations Resulting from Misalignments during DNA Synthesis 99
PART
Correcting Altered Bases in DNA: DNA Repair 107
4 Reversal of Base Damage Caused by UV Radiation 109
Direct Reversal Is an Efficient Strategy for Repairing Some Types of Base
Damage Caused by UV Radiation 109
Enzymatic Photoreactivation of Base Damage Caused by UV Radiation 109
Not All Light Dependent Recovery Effects Are Enzyme Catalyzed 110
Enzymatic Photoreactivation Was Discovered by Accident 110
Enzymes That Catalyze Photoreactivation of Cyclobutane Pyrimidine Dimers Are
Members of an Extended Family of Blue Light Receptor Proteins 112
Pyrimidine Dimer DNA Photolyases 112
Distribution of Pyrimidine Dimer DNA Photolyases in Nature 112
Measuring and Quantitating Pyrimidine Dimer DNA Photolyase Activity 113
Properties and Mechanism of Action of Pyrimidine Dimer DNA Photolyases 114
Structural Studies of Pyrimidine Dimer DNA Photolyases 119
DNA Substrate Recognition and Electron Transfer by Photoproduct DNA
Photolyases 121
Pyrimidine Dimer DNA Photolyases from Other Organisms 123
Therapeutic Use of Pyrimidine Dimer DNA Photolyase for Protection against
Sunlight 127
(6 4) Photoproduct DNA Photolyases 128
(6 4) Photoproduct DNA Photolyases Are Ubiquitous 128
Mechanism of Action of (6 4) Photoproduct DNA Photolyases 129
The C Terminal Region of (6 4) Photoproduct DNA Photolyases Is Conserved 129
Reduced Dihydroflavin Adenine Dinucleotide Is the Active Form of (6 4) Photoproduct
DNA Photolyase 131
Photolyase/Blue Light Receptor Family 131
Phylogenetic Relationships 132
Repair of Thymine Dimers by a Deoxyribozyme? 132
Photoreactivation of RNA 133
Reversal of Spore Photoproduct in DNA 133
Formation of Spore Photoproduct 133
Repair of Spore Photoproduct 134
5 1 Reversal of Alkylation Damage in DNA 139
i Adaptive Response to Alkylation Damage in Bacteria 139
A Bit of History 139
The Adaptive Response Defined 140
Adaptation to Cell Killing and Adaptation to Mutagenesis Are Independent
Processes 140
Repair of O6 Alkylguanine and O4 Alkylthymine in DNA 141
A New DNA Repair Mechanism 141
O6 Alkylguanine DNA Alkyltransferases of E. coli 142
Role of Ada Protein in the Adaptive Response to Mutagenesis 146
O6 Alkylguanine DNA Alkyltransferase II 150
DNA Alkyltransferases in Other Organisms 152
Repair of Nl Methyladenine and N3 Methylcytosine in DNA 157
alkB+ Gene of E. coli 157
Therapeutic Applications and Implications of the Repair of Alkylation Damage in
DNA 161
Genetic Polymorphisms in the 06 MGMT Gene 162
Teleological Considerations Concerning the Reversal of Alkylation Base Damage in
DNA 162
Repair of a Specific Type of Single Stranded DNA Break by Direct
Reversal 162
Summary and Conclusions 163
6 I Base Excision Repair 169
I DNA Glycosylases 169
Many DNA Glycosylases Are in the Helix Hairpin Helix Superfamily 171
Uracil DNA Glycosylases Remove Uracil from DNA 173
Some DNA Glycosylases Remove Methylated Bases 180
Several Enzymes Function To Limit Oxidized and Fragmented Purine Residues 186
DNA Glycosylases That Remove Oxidized and Fragmented Pyrimidine Residues 191
Some Organisms Have Pyrimidine Dimer DNA Glycosylases 192
Summary Comments on DNA Glycosylases 196
Apurinic/Apyrimidinic Endonucleases 197
Exonuclease III (XthA) Family of AP Endonucleases 198
Endonuclease IV (Nfo) Family of AP Endonucleases 200
Postincision Events during Base Excision Repair 202
Gap Filling and Deoxyribosephosphate Removal in E. coli 202
Gap Filling and Deoxyribosephosphate Removal in Mammalian Cells 203
Several Mechanisms Control the Fidelity of Base Excision Repair in Mammalian
Cells 204
Structure and Mechanism of DNA Ligases 204
Polynucleotide Kinase Phosphatase in Base Excision Repair 210
Poly(ADP Ribose) Polymerases in Base Excision Repair 210
Sequential Interactions between Proteins in Base Excision Repair 213
Base Excision Repair and Chromatin 214
7 I Nucleotide Excision Repair: General Features and the Process in
i Prokaryotes 227
Introduction to Nucleotide Excision Repair 227
Historical Perspectives and Terminology 227
Revised Nomenclature for Nucleotide Excision Repair 228
Nucleotide Excision Repair in E. coli 228
UvrABC DNA Damage Specific Endonuclease of E. coli 229
Damage Specific Incision of DNA during Nucleotide Excision Repair in E. coli 229
Recognition of Base Damage during Nucleotide Excision Repair in E. coli 238
DNA Incision Is Bimodal during Nucleotide Excision Repair In Prokaryotes 244
A Second Endonuclease Can Catalyze 3 DNA Incision during Nucleotide Excision Repair
in E. coli 245
Further Considerations about Nucleotide Excision Repair in Prokaryotes 247
Postincisional Events during Nucleotide Excision Repair: Excision of Damaged
Nucleotides, Repair Synthesis, and DNA Ligation 249
Long Patch Excision Repair of DNA 252
DNA Ligation 253
Miscellaneous Functions Possibly Associated with Nucleotide Excision Repair 253
Nucleotide Excision Repair in Other Prokaryotes 253
Micrococcus luteus 253
Deinococcus radiodurans 253
Other Organisms 254
Nucleotide Excision Repair Proteins Can Be Visualized in B. subtilis 254
Nucleotide Excision Repair Occurs in Some Members of the Archaea 255
Coupling of Transcription and Nucleotide Excision Repair in E. coli 255
mfd+ Gene and Transcription Repair Coupling Factor 255
Transcription Repair Coupling Factor Is Involved in Transcription Functions in the
Absence of DNA Damage 257
Detection and Measurement of Nucleotide Excision Repair in Prokaryotes 257
Excision of Damaged Bases 257
Measurement of Repair Synthesis 258
Summary 260
8 Nucleotide Excision Repair in Eukaryotes: Cell Biology and
Genetics 267
Cell Biology of Nucleotide Excision Repair in Eukaryotes 269
Experimental Demonstration of Nucleotide Excision Repair in Eukaryotic Cells 269
Kinetics of Nucleotide Excision Repair in Eukaryotic Cells 274
Genetics of Nucleotide Excision Repair in Eukaryotic Cells 274
Mammalian Cells 274
Genetics of Nucleotide Excision Repair in the Yeast S. cerevisiae 276
Genetics of Nucleotide Excision Repair in Other Eukaryotes 278
Genes and Proteins Involved in Nucleotide Excision Repair in Eukaryotes 281
Mammalian XPA and Its Yeast Ortholog RAD14 281
Replication Protein A 282
Budding Yeast RAD I and RADIO, and the Mammalian Orthologs XPF and ERCC1 284
Yeast RAD2 and Its Mammalian Ortholog, XPG 291
Yeast RAD4, Mammalian XPC, and Their Association with Rad23 Homologs 292
Yeast and Mammalian Genes That Encode Subunits of TFIIH 296
MMS19 Gene and MMS19 Protein 299
Yeast RAD7 and RAD16 Genes and Rad7 and Radl6 Proteins 299
DNA Damage Binding Protein and the Gene Defective in XP Group E 301
Understanding the Mechanism of Nucleotide Excision Repair 303
9 I Mechanism of Nucleotide Excision Repair in Eukaryotes 317
I Biochemical Strategies for Dissection of the Nucleotide Excision Repair
Mechanism 318
Nucleotide Excision Repair in Cell Extracts 318
Permeabilized Cell Systems Can Identify Factors Involved in Nucleotide Excision
Repair 320
Microinjection of DNA Repair Factors 321
Reconstitution of Nucleotide Excision Repair Defines the Minimal
Components 322
Nucleotide Excision Repair in Mammalian Cells Can Be Reconstituted with Purified
Components 322
Reconstitution of the Incision Reaction of Nucleotide Excision Repair in 5. cerevisiae with
Purified Components 323
TFIIH in Nucleotide Excision Repair: Creation of an Open Intermediate for
Dual Incision 323
TFIIH Functions Independently in Nucleotide Excision Repair and in Transcription
Initiation 323
TFIIH Harbors 10 Subunits and Two Enzymatic Activities 324
Core TFIIH Contains a Ring Like Structure 325
TFIIH Performs Helix Opening in Transcription Initiation 325
TFIIH Performs Helix Opening during Nucleotide Excision Repair 326
Additional Functions of TFIIH 326
DNA Damage Recognition Mechanism in Nucleotide Excision Repair 327
Different Lesions Have Different Repair Efficiencies and Sites of Dual Incision 327
XPC RAD23B as a Distortion Recognition Factor in Nucleotide Excision Repair 328
Bipartite Mechanism of DNA Damage Recognition during Nucleotide Excision
Repair 328
Role of DDB Protein in Nucleotide Excision Repair 331
Mechanisms of Assembly and Action of the Nucleotide Excision Repair
Machinery 331
Interactions between the Protein Components of Nucleotide Excision Repair 331
Nucleotide Excision Repair Subassemblies and Order of Action In Vitro 332
In Vivo Dynamics of Nucleotide Excision Repair 334
Repair Synthesis during Nucleotide Excision Repair 336
DNA Polymerases 8 and e and Their Participation in Nucleotide Excision Repair 336
Proliferating Cell Nuclear Antigen in Nucleotide Excision Repair 337
Replication Factor C in Nucleotide Excision Repair 338
Oligonucleotide Excision and Ligation in Nucleotide Excision Repair 339
Oligonucleotide Excision during Nucleotide Excision Repair in Eukaryotes 339
DNA Ligation during Nucleotide Excision Repair in Eukaryotes 339
DNA Topoisomerases and Nucleotide Excision Repair 339
Modulation and Regulation of Nucleotide Excision Repair in Eukaryotes 340
The Proteasome and Regulation of Nucleotide Excision Repair 340
Protein Phosphorylation Influences Nucleotide Excision Repair 342
Evolution of the Eukaryotic Nucleotide Excision Repair System 343
Eukaryotic and Prokaryotic Nucleotide Excision Repair Mechanisms Use Similar
Strategies 343
Most Eukaryotic Nucleotide Excision Repair Proteins Also Have Functions in Other
Aspects of DNA Metabolism 343
10 1 Heterogeneity of Nucleotide Excision Repair in Eukaryotic
I Genomes 351
Influence of Chromatin and Higher Order Structure on Nucleotide Excision
Repair in Mammalian Cells 351
Chromatin Is Compactly Organized yet Subject to Dynamic Reorganization 351
Chromatin Remodeling and Nucleotide Excision Repair 354
Chromatin Reassembly Coupled to Nucleotide Excision Repair 356
Other Aspects of Intragenomic Heterogeneity of Nucleotide Excision Repair 358
Nucleotide Excision Repair in Transcribed versus Nontranscribed
Regions 359
Introduction and Definition of Terms 359
Transcription Coupled Nucleotide Excision Repair 360
Proteins That Participate in Transcription Coupled Nucleotide Excision Repair 363
Cells Have Several Strategies To Deal with Stalled RNA Polymerase II 365
Biological Importance of Transcription Coupled Nucleotide Excision Repair 368
Other Aspects of Transcription Coupled Nucleotide Excision Repair 369
Summary 371
111 Alternative Excision Repair of DNA 379
i Alternative Excision Repair Involving Endonuclease V 379
Endonudease V of E. coli 379
Deoxyinosine 3 Endonuclease of E. coli 380
Endonuclease V and Deoxyinosine 3 Endonuclease of E. coli Are the Same Protein,
Encoded by the E. coli nfi+ Gene 380
Endonuclease V of E. coli Is Conserved 380
Mammalian Homolog of Endonuclease V 381
Endonuclease V of E. coli Prevents Mutations Associated with Deamination of
Bases 382
Nitrosating Agents Can Damage DNA 382
Endonuclease V of E. coli Prevents Cell Death Associated with the Presence of
Hydroxylaminopurine in DNA 383
How Does Endonuclease V Mediated Alternative Excision Repair Occur? 383
Alternative Excision Repair Mediated by Other Endonucleases 383
S. pombe DNA Endonuclease 383
S. pombe DNA Endonuclease in Other Organisms 384
What Is the Substrate Specificity of UVDE Type Endonucleases? 385
Other Substrates Recognized by UVDE Type Endonucleases 385
Uvel Dependent Alternative Excision Repair of Mitochondrial DNA in S. pombe 385
How Does Uvel Dependent Alternative Excision Repair Transpire? 386
Other Alternative Excision Repair Pathways? 386
Tyrosyl DNA Phosphodiesterase: a Repair Reaction for Topoisomerase DNA
Complexes 387
Summary 387
12 Mismatch Repair 389
; Early Biological Evidence for the Existence of Mismatch Repair 390
Genetic Phenomena Suggesting the Existence of Mismatch Repair 390
DNA Mismatch Repair in Prokaryotes 390
Mismatch Repair after Transformation of S. pneumoniae 391
In Vivo Analyses of Methyl Directed Mismatch Repair in E. coli 392
Biochemical Pathway of E. coli Methyl Directed Mismatch Repair 396
DNA Mismatch Repair in Eukaryotes 402
Early In Vivo Evidence Suggesting the Existence of Mismatch Repair in Yeasts and
Fungi 402
MutS and MutL Homologs in Eukaryotic Cells 403
Defects in Mismatch Repair Genes Are Associated with Hereditary Nonpolyposis Colon
Cancer 406
In Vitro Analyses of Mismatch Repair in Eukaryotic Cells 406
Relationship of Structure to Function of Mismatch Repair Proteins 409
MutS Structure 409
MutH Structure 411
MutL Structure 412
Unresolved Issues Concerning the Mechanism of Mismatch Repair 413
Molecular Basis of Strand Discrimination during Mismatch Repair 413
How Are Downstream Events Signaled in Mismatch Repair? 413
Effects of DNA Mismatch Repair on Genetic Recombination 416
Effect of Mismatch Repair on Recombination between Highly Homologous
Sequences 416
Effects of Mismatch Repair on Recombination between Substantially Diverged
Sequences 417
Effects of Mismatch Repair on Speciation, Adaptation, and Evolution 422
Possible Role for Mismatch Repair in Speciation 422
Cyclical Loss and Reacquisition of Mismatch Repair Play a Role in the Evolution of
Bacterial Populations 422
Effects of Mismatch Repair on Adaptive Mutagenesis 423
Special Implications of Mismatch Repair Status for Pathogenic Bacteria 424
Mismatch Repair and Meiosis 424
Roles for Mismatch Repair Proteins in Gene Conversion and Antirecombination during
Meiosis 424
Roles for Mismatch Repair Proteins in Promoting Crossovers during Meiosis 424
Mismatch Repair Proteins and DNA Damage Recognition 427
Mismatch Repair Proteins and Alkylation Damage 427
Oxidative DNA Damage and Mismatch Repair 429
Cisplatin DNA Damage and Mismatch Repair 429
Mismatch Repair and Other Forms of DNA Damage 429
Roles of Mismatch Repair Proteins in Somatic Hypermutation and Class
Switch Recombination in the Immune Response 429
Somatic Hypermutation 430
Class Switch Recombination 430
Are the Effects of Mismatch Repair Proteins on Somatic Hypermutation and Class
Switch Recombination Direct or Indirect? 430
Mismatch Repair and Cadmium Toxicity 430
Specialized Mismatch Repair Systems 431
Very Short Patch Mismatch Correction in E. coli Corrects G T Mismatches Generated by
Deamination of 5 Methylcytosine 431
Correction of G T Mismatches Generated by Deamination of 5 Methylcytosine in
Eukaryotes 433
MutY Dependent Mismatch Repair 433
13 1 Repair of Mitochondrial DNA Damage 449
I Mitochondrial DNA 449
The Mitochondrial Genome 449
Mitochondrial Mutagenesis 449
DNA Damage in the Mitochondrial Genome 451
Mitochondrial DNA Repair 451
Reversal of Base Damage in Mitochondrial DNA 452
Mitochondrial Base Excision Repair 452
Monitoring Loss of Damage from Mitochondrial DNA 453
Removal of Oxidative Damage from Mitochondrial DNA 453
Enzymes for Base Excision Repair in Mitochondrial Extracts 454
Short Patch Base Excision Repair of Mitochondrial DNA 455
Age Related Studies of Mitochondrial DNA Repair 455
Alternative Excision Repair Pathway in Mitochondria? 456
Recombinational Repair in Mitochondrial DNA? 457
Summary 457
PART 3
DNA Damage Tolerance and Mutagenesis 461
14 I The SOS Responses of Prokaryotes to DNA Damage 463
1 The SOS Responses 463
Current Model for Transcriptional Control of the SOS Response 464
Physiological and Genetic Studies Indicate the Existence of the SOS
System 465
Induced Responses 465
Genetic Studies of recA and lexA 466
Essential Elements of SOS Transcriptional Regulation 469
Proteolytic Cleavage of X Repressor during SOS Induction 470
Induction of RecA Protein 471
LexA Protein Represses Both the recA+ and lexA+ Genes 471
LexA Protein Is Proteolytically Cleaved in a RecA Dependent Fashion 472
Mechanism of LexA Repressor Cleavage 473
Similarities between LexA, X Repressor, UmuD, and Signal Peptidase 476
Nature of the RecA Interactions Necessary for LexA, UmuD, and X Repressor
Cleavage 477
Identification of Genes in the SOS Network 478
Identifying SOS Genes by the Use of Fusions 478
Identifying SOS Genes by Searching for Potential LexA Binding Sites 479
Identifying SOS Genes by Expression Microarray Analysis 479
Generation of the SOS Inducing Signal In Vivo 481
Double Strand Breaks Are Processed by the RecBCD Nuclease/Helicase To Give Single
Stranded DNA Needed for SOS Induction 483
Generation of Single Stranded DNA by Bacteriophage, Plasmids, or Transposons Leads
to SOS Induction 483
An SOS Inducing Signal Is Generated when Cells Attempt To Replicate Damaged
DNA 484
Regions of Single Stranded DNA in Undamaged Cells 485
SOS Induction Caused by Mutations That Affect the Normal Processing of DNA 485
The Special Case of Phage ct 80 Induction 486
Modeling the SOS Signal 486
Additional Subtleties in the Transcriptional Regulation of the SOS
Responses 486
Strength and Location of SOS Boxes 486
DinI, RecX, and PsiB Proteins and isfA Affect SOS Regulation by Modulating RecA
Mediated Cleavage Reactions 488
Other Regulatory Systems Can Affect the Expression of SOS Regulated Genes 489
Physiological Considerations of the SOS Regulatory Circuit 489
Levels of Control of the SOS Response besides Transcriptional
Regulation 491
A Physiological Look at the SOS Responses 491
SOS Induced Responses That Promote Survival while Maintaining the Genetic Integrity
of the Genome 491
SOS Induced Responses That Promote Survival while Destabilizing the Genetic
Integrity of the Genome 492
SOS Induced Responses That Destabilize the Genetic Integrity of the Genome 493
SOS Induced Cell Cycle Checkpoints 495
Miscellaneous Physiological Effects of SOS Induction 495
SOS Responses in Pathogenesis and Toxicology 496
Relationships of the SOS Responses to Pathogenesis 496
Use of Fusions to SOS Genes To Detect Genotoxic Agents 497
SOS Responses in Other Bacteria 497
15 I Mutagenesis and Translesion Synthesis in Prokaryotes 509
I SOS Dependent Mutagenesis: Requirements for Particular Gene
Products 510
SOS Mutagenesis by UV Radiation and Most Chemicals Is Not a Passive Process 510
UmuD and UmuC Proteins Are Important for UV Radiation and Chemical
Mutagenesis 511
Multiple Levels of Post Translational Regulation of UmuD Protein: New Dimensions to
SOS Regulation 514
Inferences about the Mechanism of SOS Mutagenesis Based on Mutational
Spectra and Site Directed Adduct Studies 523
The Original lad System: a Purely Genetic Means of Determining Mutational
Spectra 523
Mutational Spectra Obtained by Direct DNA Sequencing 524
Factors Influencing the Mutational Spectrum for a Given Mutagen 524
Influence of Transcription Coupled Excision Repair on Mutational Spectra 525
Identification of Premutagenic Lesions 525
More Complex Lesions as Premutagenic Lesions 532
SOS Mutator Effect 534
The Road to Discovering the Molecular Mechanism of SOS Mutagenesis 535
A Further Requirement for RecA Protein in SOS Mutagenesis besides Facilitating LexA
and UmuD Cleavage 535
DNA Polymerases I and II Are Not Required for SOS Mutagenesis 536
Evidence Relating DNA Polymerase III to SOS Mutagenesis 536
Influence of the Two Step Model for SOS Mutagenesis 537
Initial Efforts To Establish an In Vitro System for SOS Mutagenesis 537
UmuC Related Proteins Are Found in All Three Kingdoms of Life 538
dinB, umuDC, and mucAB Encode Members of the Y Family of Translesion DNA
Polymerases 539
Revl Catalyzes the Formation of Phosphodiester Bonds: Rad30 and Xeroderma
Pigmentosum Variant Protein Are DNA Polymerases 539
DinB Is a DNA Polymerase 539
umuDC Encodes a Translesion DNA Polymerase, DNA Pol V, That Requires Accessory
Proteins 540
mucAB Encodes a Translesion DNA Polymerase, DNA Pol Rl, That Requires Accessory
Proteins 542
The Structure of Family Y DNA Polymerases Accounts for Their Special Ability To Carry
Out Translesion Synthesis 543
Multiple SOS Induced DNA Polymerases Can Contribute to SOS Induced
Mutagenesis 543
Protein Protein Interactions That Control the Activities of the umuDC
and dinB Gene Products 543
RecA and SSB Interactions with DNA Pol V 545
Interactions of the p Sliding Clamp with DNA Polymerases V and IV 546
Interactions of UmuD and UmuD with Components of DNA Polymerase III 548
How Is Polymerase Switching Controlled? 549
What Is the Biological Significance of SOS Mutagenesis and Translesion
Synthesis by Specialized DNA Polymerases? 551
Translesion DNA Polymerases Can Contribute to Fitness and Survival in Two
Ways 551
Action of Translesion DNA Polymerases in Stationary Phase, Aging, and Stressed
Bacteria 551
SOS Independent Mutagenesis 554
Lesions That Do Not Require Induction of SOS Functions To Be Mutagenic 554
The UVM (UV Modulation of UV Mutagenesis) Response 555
Mutagenesis Resulting from the Misincorporation of Damaged Nucleotides 555
16 Recombinational Repair, Replication Fork Repair, and DNA
Damage Tolerance 569
DNA Damage Can Interfere with the Progress of Replication Forks and Lead
to the Generation of Various Structures 570
Formal Considerations 570
The In Vivo Situation Is More Complicated 571
Transient Partial Inhibition of DNA Replication after DNA Damage 573
Various DNA Structures Resulting Directly or Indirectly from DNA Damage
Can Be Processed by Homologous Recombination Proteins 574
RecA Protein: a Protein with Mechanistic Roles in Homologous Recombination and
DNA Repair 574
Other Key Proteins with Roles in Homologous Recombination 579
Recombinational Repair of Double Strand Breaks in E. coli 584
Model for Damage Tolerance Involving the Recombinational Repair of
Daughter Strand Gaps 586
Evidence Supporting the Model for Recombinational Repair of Daughter Strand
Gaps 586
Perspectives on Daughter Strand Gap Repair 590
An Error Free Process(es) Involving Recombination Functions Predominates over
Mutagenic Translesion Replication in a Model In Vivo System 592
Homologous Recombination Functions Play Critical Roles in the Stabilization
and Recovery of Arrested or Collapsed Replication Forks 593
Recognition of Fundamental Relationships between Replication and
Recombination 593
Possible Mechanisms for Regressing Replication Forks 598
Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks
Arrested by a Lesion Affecting Only One Strand of the DNA Template 599
Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks
Arrested by a Lesion or Blocks Affecting Both Strands of the DNA Template 602
Recovery of DNA Replication after DNA Damage: Inducible Replisome
Reactivation/Replication Restart 603
Polymerases Participating in Inducible Replisome Reactivation/Replication Restart
Revisited 603
17 DNA Damage Tolerance and Mutagenesis in Eukaryotic Cells 613
Phenomenology of UV Radiation Induced Mutagenesis in the Yeast
Saccharomyces cerevisiae 613
Insights from Mutational Spectra: the SUP4 0 System 613
Studies with Photoproducts at Defined Sites 615
Untargeted Mutagenesis in S. cerevisiae Cells Exposed to UV Radiation 616
Timing and Regulation of UV Radiation Induced Mutagenesis 616
Phenomenology of UV Radiation Induced Mutagenesis in Mammalian
Cells 617
DNA Replication in UV Irradiated Cells 617
Inducibility of Mutagenic Processes in Mammalian Cells? 621
Mutational Specificity of UV Radiation Induced Lesions 622
Summary and Conclusions 629
Molecular Mechanisms of Eukaryotic DNA Damage Tolerance and
Mutagenesis 629
Genetic Framework in S. cerevisiae 629
DNA Polymerase £ 629
Revl Protein 631
DNA Polymerase r 632
Other Vertebrate Lesion Bypass Polymerases 636
Handling of DNA Lesions by Bypass Polymerases: Synopsis and Comparison with In
Vivo Data 638
Somatic Hypermutation 639
The RAD6 Epistasis Group Dissected: Denning Error Prone and Error Free Tolerance
Mechanisms 642
Role of PCNA in Orchestrating the Choice of Damage Tolerance Pathways 647
Summary and Conclusions 649
18 1 Managing DNA Strand Breaks in Eukaryotic Cells: Repair
I Pathway Overview and Homologous Recombination 663
Overview of Various Pathways for Double Strand Break Repair in
Eukaryotes 663
Saccharomyces cerevisiae as a Model System for Detecting Double Strand Breaks
and Their Repair 665
Experimental Systems To Study Responses to Localized DNA Double Strand
Breaks 668
The HO Endonuclease System 668
Generation of Double Strand Breaks in Conditional Dicentric Chromosomes 668
I Scel Induced Targeted Double Strand Breaks 669
Homologous Recombination 671
End Processing as the Initiating Step 671
Pairing and Exchanging of Homologous DNA: Rad51, Its Orthologs, Paralogs, and
Interacting Partners 671
Role of Cohesin Proteins 681
The BRCA/Fanconi Pathway 682
Holliday Structure Resolution 685
Synthesis Dependent Strand Annealing and Break Induced
Replication 687
Single Strand Annealing 688
Transcription and Recombination 689
UV Radiation Stimulated Recombination 690
Repair of DNA Interstrand Cross Links 690
Interstrand Cross Link Repair in E. coli 691
Interstrand Cross Link Repair in S. cerevisiae 692
Interstrand Cross Link Repair in Higher Eukaryotes 695
Summary 696
19 | Managing DNA Strand Breaks in Eukaryotic Cells:
I Nonhomologous End Joining and Other Pathways 711
Nonhomologous End Joining 711
Introduction 711
V(D)J Recombination 712
Class Switch Recombination 714
Roles of the Ku Proteins 715
DNA Dependent Protein Kinase 718
Artemis: a Human SCID Syndrome Reveals a Player in Nonhomologous End
Joining 721
Ligation Step of Nonhomologous End Joining 722
Synopsis: Model for Vertebrate Nonhomologous End Joining 724
TheMrell Rad50 NBSl/Xrs2 Complex 724
Yeast Rad50, Mrel 1, and Xrs2 Function in Double Strand Break Repair and Meiosis
but Are Not Essential for Homologous Recombination 725
Two MRN Complex Components Are Associated with Human Genomic Instability
Syndromes 726
Null Mutations of MRN Components Are Lethal in Mammalian Cells, and
Hypomorphic Mutations Result in Severe Developmental Consequences 726
Focus Formation of the MRN Complex at Sites of Double Strand Breaks 727
In Vitro DNA Processing Activities of the MRN Complex 727
The MRN Complex in Nonhomologous DNA End Joining: a Major Role in 5. cerevisiae
but Possibly Not in Vertebrates 728
Role of the MRN Complex in Homologous Recombination 730
Significance of Nuclease Activity 731
Special Roles of the MRN Complex in Replication and Telomere Maintenance 731
Molecular Velcro and Beyond: Models for MRN Action Based on Structural
Analysis 733
Conclusions 734
Histone Modifications and Double Strand Breaks 735
Histone Phosphorylation 735
Histone Acetylation 736
Regulation of Pathway Choice 736
Repair of Single Strand Breaks 737
Sources and Significance of Single Strand Breaks 737
Poly(ADP Ribose) Polymerase as a Nick Sensor 738
XRCC1 Is a Scaffold Protein Orchestrating Interactions among Multiple Single Strand
Break Repair Proteins 738
PART 4
Regulatory Responses to DNA Damage in Eukaryotes 751
20 I Cell Cycle Checkpoints: General Introduction and Mechanisms of
1 DNA Damage Sensing 753
Cell Cycle Basics and the Emergence of the Checkpoint Concept 753
Studying Checkpoints 757
DNA Damage Sensing 758
Defining Checkpoint Triggering Damage and Sensor Proteins 758
The ATM Protein as a Damage Sensor 760
ATR Protein and Its Targeting Subunit 762
PCNA and RFC Like Clamp and Clamp Loader Complexes 764
Cross Talk between Sensors 765
The MRN Complex Plays an Additional Role in Checkpoint Arrests 766
Synopsis: Independent but Communicating Sensors Are Brought Together by Common
Requirements 767
Other Sensor Candidates 768
Sensing UV Radiation Damage 768
Damage Sensing in S Phase 769
211 Cell Cycle Checkpoints: Signal Transmission and Effector
I Targets 779
Generation and Transmission of a Checkpoint Activating Signal 779
The Rad53Sc/CdslSp/CHK2Hs Kinase 779
Mediators Are Important for Activation of Rad53Sc/CdslSp/CHK2Hs through DNA
Structure Sensors 781
Possible Mammalian Rad9Sc Homologs 782
S Phase Specific Activation of Rad53Sc/CdslSp/CHK2Hs 783
Chkl Kinase: Different Roles in Different Organisms 783
Activation of Chkl Kinase in 5. pombe, X. lams, and Humans 784
Summary: Pathways of Generating a Transmittable Damage Signal 784
Downstream Targets and Mechanisms That Regulate Cell Cycle
Progression 785
p53 as a Target of DNA Checkpoint Pathways 785
DNA Damage Induced G,/S Arrest 791
Modulation of S Phase in the Presence of DNA Damage 794
DNA Damage Induced G2/M Arrest 798
DNA Damage and the Regulation of M Phase 801
Synopsis 802
Effector Targets That Modulate DNA Repair 802
Repair Targets in Yeasts 802
Repair Targets in Mammalian Cells 803
Other Regulatory Responses to DNA Damage 803
Summary 804
22 I Transcriptional Responses to DNA Damage 817
I Introduction 817
Phenotypic Characterization of Pathway Inducibility 817
Analysis of Individual Genes 817
Differential Screening 818
Screens of Genome Arrays 818
Saccharomyces cerevisiae Genes Regulated in Response to DNA Damaging
Agents 818
Regulation of Ribonucleotide Reductase 818
Inducibility of Genes Involved in DNA Repair and Damage Tolerance: a Look at Various
Pathways 820
Genome Wide Approaches 823
Synopsis: No Satisfying Answer to the Question of Significance 827
Vertebrate Genes Regulated in Response to DNA Damaging Agents 828
Overview 828
p53 as a Transcription Factor 828
E2F Transcription Factor Family 830
Mammalian UV Radiation Response 831
Transcriptional Response to Ionizing Radiation 835
Summary and Conclusions 837
23 1 DNA Damage and the Regulation of Cell Fate 845
1 Adaptation and Cell Cycle Restart 846
Damage Signaling and Adaptation in Saccharomyces cerevisiae 846
Adaptation and Cell Cycle Restart by Silencing of Downstream Effectors 847
Recovery in Multicellular Eukaryotes 847
Regulation of Apoptosis 848
Introduction to Apoptotic Pathways 848
Activation of the Apoptosis Pathway by DNA Damage: the Roles of p53 Revisited 850
Role of DNA Damage Sensors and Transducers in Apoptosis 852
Additional Elements of DNA Damage Induced Apoptosis 853
Senescence, Cancer, and the DNA Damage Connection 854
Checkpoints and Cancer Therapy 856
PART 5
Disease States Associated with Defective Biological
Responses to DNA Damage 863
24 I Xeroderma Pigmentosum: a Disease Associated with Defective
i Nucleotide Excision Repair or Defective Translesion DNA
Synthesis 865
A Huge Literature on Xeroderma Pigmentosum 865
Primary Clinical Features 866
Other Clinical Features 867
Incidence and Demographics 867
Skin Cancer Associated with Xeroderma Pigmentosum 868
Phenotypes of Xeroderma Pigmentosum Cells 868
Chromosomal Abnormalities 868
Sensitivity to Killing by DNA Damaging Agents 869
Hypermutability 869
Source of Mutations 869
Defective Nucleotide Excision Repair 870
Repair of Oxidative Damage and Its Relationship to Neurological Disorders in
Xeroderma Pigmentosum 872
Defective Repair of Purine Cyclodeoxynucleosides 873
Genetic Complexity of Xeroderma Pigmentosum 874
The Xeroderma Pigmentosum Heterozygous State 875
Molecular Pathology 875
Xeroderma Pigmentosum from Genetic Complementation Group A 875
Xeroderma Pigmentosum from Genetic Complementation Group B 876
Xeroderma Pigmentosum from Genetic Complementation Group C 877
Xeroderma Pigmentosum from Genetic Complementation Group D 878
Xeroderma Pigmentosum from Genetic Complementation Group E 880
Mutations Have Only Been Found in the DDB2 Gene in XP E Group Cells 880
Xeroderma Pigmentosum from Genetic Complementation Group F 880
Xeroderma Pigmentosum from Genetic Complementation Group G 881
Summary 881
Unexplained Features of Xeroderma Pigmentosum 881
Cancer in Other Organs in Xeroderma Pigmentosum Individuals 881
Cancer Risk Assessment 882
Pathogenesis of Neurological Complications 882
Therapy 882
Mouse Models of Defective Nucleotide Excision Repair 882
Mice Defective in the Xpa Gene 883
Mice Defective in the Xpc Gene 884
Mice Defective in the Xpd Gene 886
Mice Defective in the Xpe Gene 886
Mice Defective in the Xpf Gene 887
Mice Defective in the Xpg Gene 887
Mice Defective in the Erccl Gene 887
Mice Defective in the Rad23A and Rad23B Genes 887
Summary 887
25 I Other Diseases Associated with Defects in Nucleotide Excision
I Repair of DNA 895
Cockayne Syndrome 895
Introduction 895
Clinical Phenotypes 895
Cellular Phenotypes 896
Genetics 898
Other Clinical Entities Associated with Mutations in Cockayne Syndrome or
XP Genes 905
Cerebro Oculo Facio Skeletal Syndrome 905
UV Sensitive Syndrome 905
Combined XP/CS Complex 906
Allelic Heterogeneity in Xeroderma Pigmentosum 906
Trichothiodystrophy 907
The Transcription Syndrome Hypothesis of XP/CS and Trichothiodystrophy 909
Direct Observations of Defective Transcription 910
Molecular Defects in XP/CS and Trichothiodystrophy Cells 910
Allele Specific and Gene Dosage Effects in This Group of Diseases 912
Skin Cancer in the Transcription Syndromes 913
Summary 913
26 I Diseases Associated with Defective Responses to DNA Strand
I Breaks 919
Ataxia Telangiectasia (Louis Bar Syndrome) 919
Clinical Features 919
Cellular Phenotypes 920
Identification of the Ataxia Telangiectasia Mutated (ATM) Gene 924
Aim Mutant Mice 926
Nijmegen Breakage Syndrome 928
Clinical Features 928
Cellular Characteristics 928
Identification of the Gene Mutated in Nijmegen Breakage Syndrome (NBS1) 929
Nihrin and Nijmegen Breakage Syndrome Cellular Phenotypes 929
Nbsl Mutant Mice 929
Genetic Heterogeneity 929
Heterozygosity and Cancer Predisposition 930
Ataxia Telangiectasia Like Disorder 930
DNA Ligase IV Mutations and Human Disease 930
Seckel Syndrome 930
Severe Combined Immunodeficiency 932
Clinical Features 933
Molecular Causes 934
Recombinase Activating Gene Deficiencies (RAG1 or Ry4G2 Deficient Severe Combined
Immunodeficiency) 935
Animal Models 935
Spinocerebellar Ataxia with Axonal Neuropathy 935
27 I Diseases Associated with Disordered DNA Helicase Function 947
i Biochemistry of RecQ Helicases 947
Crystal Structures of DNA Helicases 949
Fluorescence Resonance Energy Transfer 950
DNA Helicases That Participate in DNA Replication 952
RecQ Helicases and Human Disease 953
RecQ Helicases in Model Organisms 953
RecQ Protein in E. coli 953
Yeast Homologs of RecQ 954
Bloom Syndrome 954
Clinical Features of Bloom Syndrome Include a Marked Cancer Predisposition 955
Autosomal Recessive Genetics of Bloom Syndrome 955
Chromosome Instability as a Hallmark of Bloom Syndrome Cells 955
Bloom Syndrome Cells Exhibit Defects Associated with the S Phase of the Cell
Cycle 956
Bloom Syndrome Cells Manifest a Diversity of Subtle Defects in Enzymes Involved in
DNA Repair 957
Somatic Recombination Events in Bloom Syndrome Cells Facilitate Mapping and
Cloning of the BLM Gene 958
Interallelic Recombination and Its Potential Relevance to Bloom Syndrome 958
The BLM Gene Is a Member of the RecQ Family 958
Bloom Syndrome Heterozygotes May Be Predisposed to Cancer 959
The BLM Gene Product Is a RecQ Like Helicase 960
BLM Gene Expression 960
BLM Protein Localization 961
Modulation of Sister Chromatid Exchange 961
Association of BLM with Other DNA Repair Functions 962
Models for the Study of BLM Function 963
The Molecular Function of BLM Protein 964
Werner Syndrome 965
Clinical Features 965
Genetics 966
Cellular Phenotype of Werner Syndrome Cells 966
Identification of the WRN Gene 966
WRN Protein Contains DNA Helicase and Exonuclease Activities 967
WRN Protein Interactions 967
WRN Expression 968
WRN Protein Function 968
Mutations in RECQL4 Are Associated with Rothmund Thomson Syndrome
and RAPADILINO Syndrome 968
Clinical Features of Rothmund Thomson Syndrome 968
Cellular Characteristics of Rothmund Thomson Syndrome 968
Rothmund Thomson Syndrome Patients Have Mutations in RECQL4 969
RAPADILINO Syndrome 969
Summary of Human Diseases Associated with Defects in the RecQ Family of
DNA Helicase 971
28 I Additional Diseases Associated with Defective Responses to DNA
I Damage 979
Hereditary Nonpolyposis Colon Cancer 980
Clinical Presentation 980
Hereditary Nonpolyposis Colon Cancer and Microsatellite Instability 980
Hereditary Nonpolyposis Colon Cancer and Mismatch Repair 981
How Do Heterozygous Mutations Cause Cancer? 984
Mouse Models with Defects in Mismatch Repair Genes 985
Tumors in Homozygous Mutant Mice 985
Fanconi Anemia 986
Clinical Phenotypes 987
Genetics 988
Cellular Features 988
DNA Repair in Fanconi Anemia Cells 989
Genetic Complexity 989
Mouse Models 993
Final Comments 994
29 I Hereditary Diseases That Implicate Defective Responses to DNA
I Damage 1001
Hereditary Cancer Predisposition Syndromes 1001
Retinoblastoma 1004
Li Fraumeni Syndrome 1006
Breast Cancer Predisposition Syndromes 1007
Predisposition to Gastrointestinal Tumors 1008
Skin Cancer Syndromes 1016
Additional Cancer Predisposition Syndromes 1018
Disorders with Alterations in Chromatin Structure 1021
Immunodeficiency Centromeric Instability Facial Anomalies Syndrome 1021
Roberts Syndrome 1023
Alpha Thalassemia/Mental Retardation Syndrome, X Linked 1025
Rett Syndrome 1025
Rubinstein Taybi Syndrome 1026
Coffin Lowry Syndrome 1026
Saethre Chotzen Syndrome 1026
Dyskeratosis Congenita 1027
DNA Repair and Its Association with Aging 1028
Aging and the Age Related Decline in DNA Repair 1028
Reversal of Aging and DNA Repair 1030
Array Analysis of Aging in Mammals 1030
Engineered Mouse Models for Aging 1030
Telomeres and Aging 1031
Hutchinson Gilford Progeria Syndrome (Progeria) 1032
Down Syndrome (Trisomy 21) 1033
30 | DNA Polymorphisms in Gatekeeper and Guardian Genes 1049
I Human Genetic Variation 1050
DNA Structure/Repair Related Methodologies for Single Nucleotide
Polymorphism Detection 1052
Oligonucleotide Arrays 1052
Mismatch Repair Detection 1054
TDG/MutY Glycosylase Mismatch Detection 1054
MassEXTEND 1054
Stabilized Double D Loops 1054
Assessing the Role of DNA Repair Gene Polymorphisms in Disease 1056
Statistics and Population Based Studies 1056
Variability in DNA Repair Capacity 1057
Heterozygosity and DNA Repair Gene Mutations 1059
Heterozygosity for Genes Associated with Dominantly Inherited Disorders 1059
Heterozygosity for Genes Associated with Recessive Disorders 1061
Summarizing the Role of Heterozygosity 1061
DNA Repair Gene Polymorphisms 1062
DNA Repair Gene Single Nucleotide Polymorphism Discovery 1062
Polymorphisms That Impact the Levels of Chemical Induced DNA Damage 1062
Cytochrome P 450 Monooxygenase Gene 1062
Glutathione S Transferase Ml Gene 1063
iV Acetyltransferase 2 Gene 1063
DNA Repair Gene Polymorphisms and Putative Cancer Risk 1064
Pharmacogenomics and DNA Repair Gene Polymorphisms 1067
Polymorphic Alleles and Functional Defects 1067
Summary 1070
Appendix 1081
Table 1 Nomenclature of DNA repair genes 1081
Table 2 Human hereditary diseases and defective cellular responses to DNA
damage 1087
Index 1091
|
| adam_txt |
Contents
Preface xxv
Abbreviations xxix
PART 1
Sources and Consequences of DNA Damage 1
1 I Introduction: Biological Responses to DNA Damage 3
I Historical Reflections 3
The Problem of Constant Genomic Insult 4
Biological Responses to DNA Damage 4
DNA Repair 4
DNA Damage Tolerance and Mutagenesis 5
Other Responses to DNA Damage 6
Disease States Associated with Defective Responses to DNA Damage 6
2 I DNA Damage 9
I Endogenous DNA Damage 9
Spontaneous Alterations in DNA Base Chemistry 9
Mismatches Created by DNA Replication Errors 24
Environmental DNA Damage 25
DNA Damage by Radiation 25
Chemical Agents That Damage DNA 35
DNA Damage and Chromatin Structure 48
UV Photoproduct Formation Is Influenced by Chromatin Structure1 and Binding of Oilier
Proteins 48
Chromosomal Structure and Bound Proteins Can Protect against DNA Damage in
Bacteria 49
Detection of DNA Damage by Proteins 50
Structural Information Is Encoded in DNA 50
Binding to Single Stranded DNA 54
Locating Sites of DNA Damage 55
Summary and Conclusions 57
vii
3 Introduction to Mutagenesis 71
Mutations and Mutants: Some Definitions 71
Point Mutations and Other Classes of Mutations 73
Base Substitution Mutations 73
Mutations Resulting from the Addition or Deletion of Small Numbers of Base Pairs 74
Systems Used To Detect and Analyze Mutations 75
Early Systems for the Analysis of Mutagenesis 75
The Ames Salmonella Test: a Widely Used Reversion System 76
E. coli Lad: an Example of a Forward Mutational System 77
Other Examples of Forward Mutational Systems 78
Special Systems To Detect Frameshift or Deletion Mutations 78
Analysis of Mutagenesis in Mammalian Cells 79
Use of Site Specific Adducts 85
Replication Fidelity and DNA Polymerase Structure 86
Templated Information in DNA 86
Energetics of Base Pairing 87
Geometric Selection of Nucleotides during DNA Synthesis 87
A Two Metal Ion Mechanism for DNA Synthesis 90
Open and Closed Conformations of DNA Polymerases 92
Importance of Base Pairing Geometry versus Hydrogen Bonds 92
Selection against Ribonucleotides 93
Proofreading during DNA Synthesis 93
Lesion Bypass by Error Prone DNA Polymerases 95
Conclusions about Replicative Fidelity 98
Mechanisms Contributing to Spontaneous Mutagenesis 98
Base Substitution Mutations Resulting from Misincorporation during DNA Synthesis 98
Mutations Resulting from Misalignments during DNA Synthesis 99
PART
Correcting Altered Bases in DNA: DNA Repair 107
4 Reversal of Base Damage Caused by UV Radiation 109
Direct Reversal Is an Efficient Strategy for Repairing Some Types of Base
Damage Caused by UV Radiation 109
Enzymatic Photoreactivation of Base Damage Caused by UV Radiation 109
Not All Light Dependent Recovery Effects Are Enzyme Catalyzed 110
Enzymatic Photoreactivation Was Discovered by Accident 110
Enzymes That Catalyze Photoreactivation of Cyclobutane Pyrimidine Dimers Are
Members of an Extended Family of Blue Light Receptor Proteins 112
Pyrimidine Dimer DNA Photolyases 112
Distribution of Pyrimidine Dimer DNA Photolyases in Nature 112
Measuring and Quantitating Pyrimidine Dimer DNA Photolyase Activity 113
Properties and Mechanism of Action of Pyrimidine Dimer DNA Photolyases 114
Structural Studies of Pyrimidine Dimer DNA Photolyases 119
DNA Substrate Recognition and Electron Transfer by Photoproduct DNA
Photolyases 121
Pyrimidine Dimer DNA Photolyases from Other Organisms 123
Therapeutic Use of Pyrimidine Dimer DNA Photolyase for Protection against
Sunlight 127
(6 4) Photoproduct DNA Photolyases 128
(6 4) Photoproduct DNA Photolyases Are Ubiquitous 128
Mechanism of Action of (6 4) Photoproduct DNA Photolyases 129
The C Terminal Region of (6 4) Photoproduct DNA Photolyases Is Conserved 129
Reduced Dihydroflavin Adenine Dinucleotide Is the Active Form of (6 4) Photoproduct
DNA Photolyase 131
Photolyase/Blue Light Receptor Family 131
Phylogenetic Relationships 132
Repair of Thymine Dimers by a Deoxyribozyme? 132
Photoreactivation of RNA 133
Reversal of Spore Photoproduct in DNA 133
Formation of Spore Photoproduct 133
Repair of Spore Photoproduct 134
5 1 Reversal of Alkylation Damage in DNA 139
i Adaptive Response to Alkylation Damage in Bacteria 139
A Bit of History 139
The Adaptive Response Defined 140
Adaptation to Cell Killing and Adaptation to Mutagenesis Are Independent
Processes 140
Repair of O6 Alkylguanine and O4 Alkylthymine in DNA 141
A New DNA Repair Mechanism 141
O6 Alkylguanine DNA Alkyltransferases of E. coli 142
Role of Ada Protein in the Adaptive Response to Mutagenesis 146
O6 Alkylguanine DNA Alkyltransferase II 150
DNA Alkyltransferases in Other Organisms 152
Repair of Nl Methyladenine and N3 Methylcytosine in DNA 157
alkB+ Gene of E. coli 157
Therapeutic Applications and Implications of the Repair of Alkylation Damage in
DNA 161
Genetic Polymorphisms in the 06 MGMT Gene 162
Teleological Considerations Concerning the Reversal of Alkylation Base Damage in
DNA 162
Repair of a Specific Type of Single Stranded DNA Break by Direct
Reversal 162
Summary and Conclusions 163
6 I Base Excision Repair 169
I DNA Glycosylases 169
Many DNA Glycosylases Are in the Helix Hairpin Helix Superfamily 171
Uracil DNA Glycosylases Remove Uracil from DNA 173
Some DNA Glycosylases Remove Methylated Bases 180
Several Enzymes Function To Limit Oxidized and Fragmented Purine Residues 186
DNA Glycosylases That Remove Oxidized and Fragmented Pyrimidine Residues 191
Some Organisms Have Pyrimidine Dimer DNA Glycosylases 192
Summary Comments on DNA Glycosylases 196
Apurinic/Apyrimidinic Endonucleases 197
Exonuclease III (XthA) Family of AP Endonucleases 198
Endonuclease IV (Nfo) Family of AP Endonucleases 200
Postincision Events during Base Excision Repair 202
Gap Filling and Deoxyribosephosphate Removal in E. coli 202
Gap Filling and Deoxyribosephosphate Removal in Mammalian Cells 203
Several Mechanisms Control the Fidelity of Base Excision Repair in Mammalian
Cells 204
Structure and Mechanism of DNA Ligases 204
Polynucleotide Kinase Phosphatase in Base Excision Repair 210
Poly(ADP Ribose) Polymerases in Base Excision Repair 210
Sequential Interactions between Proteins in Base Excision Repair 213
Base Excision Repair and Chromatin 214
7 I Nucleotide Excision Repair: General Features and the Process in
i Prokaryotes 227
Introduction to Nucleotide Excision Repair 227
Historical Perspectives and Terminology 227
Revised Nomenclature for Nucleotide Excision Repair 228
Nucleotide Excision Repair in E. coli 228
UvrABC DNA Damage Specific Endonuclease of E. coli 229
Damage Specific Incision of DNA during Nucleotide Excision Repair in E. coli 229
Recognition of Base Damage during Nucleotide Excision Repair in E. coli 238
DNA Incision Is Bimodal during Nucleotide Excision Repair In Prokaryotes 244
A Second Endonuclease Can Catalyze 3' DNA Incision during Nucleotide Excision Repair
in E. coli 245
Further Considerations about Nucleotide Excision Repair in Prokaryotes 247
Postincisional Events during Nucleotide Excision Repair: Excision of Damaged
Nucleotides, Repair Synthesis, and DNA Ligation 249
Long Patch Excision Repair of DNA 252
DNA Ligation 253
Miscellaneous Functions Possibly Associated with Nucleotide Excision Repair 253
Nucleotide Excision Repair in Other Prokaryotes 253
Micrococcus luteus 253
Deinococcus radiodurans 253
Other Organisms 254
Nucleotide Excision Repair Proteins Can Be Visualized in B. subtilis 254
Nucleotide Excision Repair Occurs in Some Members of the Archaea 255
Coupling of Transcription and Nucleotide Excision Repair in E. coli 255
mfd+ Gene and Transcription Repair Coupling Factor 255
Transcription Repair Coupling Factor Is Involved in Transcription Functions in the
Absence of DNA Damage 257
Detection and Measurement of Nucleotide Excision Repair in Prokaryotes 257
Excision of Damaged Bases 257
Measurement of Repair Synthesis 258
Summary 260
8 Nucleotide Excision Repair in Eukaryotes: Cell Biology and
Genetics 267
Cell Biology of Nucleotide Excision Repair in Eukaryotes 269
Experimental Demonstration of Nucleotide Excision Repair in Eukaryotic Cells 269
Kinetics of Nucleotide Excision Repair in Eukaryotic Cells 274
Genetics of Nucleotide Excision Repair in Eukaryotic Cells 274
Mammalian Cells 274
Genetics of Nucleotide Excision Repair in the Yeast S. cerevisiae 276
Genetics of Nucleotide Excision Repair in Other Eukaryotes 278
Genes and Proteins Involved in Nucleotide Excision Repair in Eukaryotes 281
Mammalian XPA and Its Yeast Ortholog RAD14 281
Replication Protein A 282
Budding Yeast RAD I and RADIO, and the Mammalian Orthologs XPF and ERCC1 284
Yeast RAD2 and Its Mammalian Ortholog, XPG 291
Yeast RAD4, Mammalian XPC, and Their Association with Rad23 Homologs 292
Yeast and Mammalian Genes That Encode Subunits of TFIIH 296
MMS19 Gene and MMS19 Protein 299
Yeast RAD7 and RAD16 Genes and Rad7 and Radl6 Proteins 299
DNA Damage Binding Protein and the Gene Defective in XP Group E 301
Understanding the Mechanism of Nucleotide Excision Repair 303
9 I Mechanism of Nucleotide Excision Repair in Eukaryotes 317
I Biochemical Strategies for Dissection of the Nucleotide Excision Repair
Mechanism 318
Nucleotide Excision Repair in Cell Extracts 318
Permeabilized Cell Systems Can Identify Factors Involved in Nucleotide Excision
Repair 320
Microinjection of DNA Repair Factors 321
Reconstitution of Nucleotide Excision Repair Defines the Minimal
Components 322
Nucleotide Excision Repair in Mammalian Cells Can Be Reconstituted with Purified
Components 322
Reconstitution of the Incision Reaction of Nucleotide Excision Repair in 5. cerevisiae with
Purified Components 323
TFIIH in Nucleotide Excision Repair: Creation of an Open Intermediate for
Dual Incision 323
TFIIH Functions Independently in Nucleotide Excision Repair and in Transcription
Initiation 323
TFIIH Harbors 10 Subunits and Two Enzymatic Activities 324
Core TFIIH Contains a Ring Like Structure 325
TFIIH Performs Helix Opening in Transcription Initiation 325
TFIIH Performs Helix Opening during Nucleotide Excision Repair 326
Additional Functions of TFIIH 326
DNA Damage Recognition Mechanism in Nucleotide Excision Repair 327
Different Lesions Have Different Repair Efficiencies and Sites of Dual Incision 327
XPC RAD23B as a Distortion Recognition Factor in Nucleotide Excision Repair 328
Bipartite Mechanism of DNA Damage Recognition during Nucleotide Excision
Repair 328
Role of DDB Protein in Nucleotide Excision Repair 331
Mechanisms of Assembly and Action of the Nucleotide Excision Repair
Machinery 331
Interactions between the Protein Components of Nucleotide Excision Repair 331
Nucleotide Excision Repair Subassemblies and Order of Action In Vitro 332
In Vivo Dynamics of Nucleotide Excision Repair 334
Repair Synthesis during Nucleotide Excision Repair 336
DNA Polymerases 8 and e and Their Participation in Nucleotide Excision Repair 336
Proliferating Cell Nuclear Antigen in Nucleotide Excision Repair 337
Replication Factor C in Nucleotide Excision Repair 338
Oligonucleotide Excision and Ligation in Nucleotide Excision Repair 339
Oligonucleotide Excision during Nucleotide Excision Repair in Eukaryotes 339
DNA Ligation during Nucleotide Excision Repair in Eukaryotes 339
DNA Topoisomerases and Nucleotide Excision Repair 339
Modulation and Regulation of Nucleotide Excision Repair in Eukaryotes 340
The Proteasome and Regulation of Nucleotide Excision Repair 340
Protein Phosphorylation Influences Nucleotide Excision Repair 342
Evolution of the Eukaryotic Nucleotide Excision Repair System 343
Eukaryotic and Prokaryotic Nucleotide Excision Repair Mechanisms Use Similar
Strategies 343
Most Eukaryotic Nucleotide Excision Repair Proteins Also Have Functions in Other
Aspects of DNA Metabolism 343
10 1 Heterogeneity of Nucleotide Excision Repair in Eukaryotic
I Genomes 351
Influence of Chromatin and Higher Order Structure on Nucleotide Excision
Repair in Mammalian Cells 351
Chromatin Is Compactly Organized yet Subject to Dynamic Reorganization 351
Chromatin Remodeling and Nucleotide Excision Repair 354
Chromatin Reassembly Coupled to Nucleotide Excision Repair 356
Other Aspects of Intragenomic Heterogeneity of Nucleotide Excision Repair 358
Nucleotide Excision Repair in Transcribed versus Nontranscribed
Regions 359
Introduction and Definition of Terms 359
Transcription Coupled Nucleotide Excision Repair 360
Proteins That Participate in Transcription Coupled Nucleotide Excision Repair 363
Cells Have Several Strategies To Deal with Stalled RNA Polymerase II 365
Biological Importance of Transcription Coupled Nucleotide Excision Repair 368
Other Aspects of Transcription Coupled Nucleotide Excision Repair 369
Summary 371
111 Alternative Excision Repair of DNA 379
i Alternative Excision Repair Involving Endonuclease V 379
Endonudease V of E. coli 379
Deoxyinosine 3' Endonuclease of E. coli 380
Endonuclease V and Deoxyinosine 3' Endonuclease of E. coli Are the Same Protein,
Encoded by the E. coli nfi+ Gene 380
Endonuclease V of E. coli Is Conserved 380
Mammalian Homolog of Endonuclease V 381
Endonuclease V of E. coli Prevents Mutations Associated with Deamination of
Bases 382
Nitrosating Agents Can Damage DNA 382
Endonuclease V of E. coli Prevents Cell Death Associated with the Presence of
Hydroxylaminopurine in DNA 383
How Does Endonuclease V Mediated Alternative Excision Repair Occur? 383
Alternative Excision Repair Mediated by Other Endonucleases 383
S. pombe DNA Endonuclease 383
S. pombe DNA Endonuclease in Other Organisms 384
What Is the Substrate Specificity of UVDE Type Endonucleases? 385
Other Substrates Recognized by UVDE Type Endonucleases 385
Uvel Dependent Alternative Excision Repair of Mitochondrial DNA in S. pombe 385
How Does Uvel Dependent Alternative Excision Repair Transpire? 386
Other Alternative Excision Repair Pathways? 386
Tyrosyl DNA Phosphodiesterase: a Repair Reaction for Topoisomerase DNA
Complexes 387
Summary 387
12 Mismatch Repair 389
; Early Biological Evidence for the Existence of Mismatch Repair 390
Genetic Phenomena Suggesting the Existence of Mismatch Repair 390
DNA Mismatch Repair in Prokaryotes 390
Mismatch Repair after Transformation of S. pneumoniae 391
In Vivo Analyses of Methyl Directed Mismatch Repair in E. coli 392
Biochemical Pathway of E. coli Methyl Directed Mismatch Repair 396
DNA Mismatch Repair in Eukaryotes 402
Early In Vivo Evidence Suggesting the Existence of Mismatch Repair in Yeasts and
Fungi 402
MutS and MutL Homologs in Eukaryotic Cells 403
Defects in Mismatch Repair Genes Are Associated with Hereditary Nonpolyposis Colon
Cancer 406
In Vitro Analyses of Mismatch Repair in Eukaryotic Cells 406
Relationship of Structure to Function of Mismatch Repair Proteins 409
MutS Structure 409
MutH Structure 411
MutL Structure 412
Unresolved Issues Concerning the Mechanism of Mismatch Repair 413
Molecular Basis of Strand Discrimination during Mismatch Repair 413
How Are Downstream Events Signaled in Mismatch Repair? 413
Effects of DNA Mismatch Repair on Genetic Recombination 416
Effect of Mismatch Repair on Recombination between Highly Homologous
Sequences 416
Effects of Mismatch Repair on Recombination between Substantially Diverged
Sequences 417
Effects of Mismatch Repair on Speciation, Adaptation, and Evolution 422
Possible Role for Mismatch Repair in Speciation 422
Cyclical Loss and Reacquisition of Mismatch Repair Play a Role in the Evolution of
Bacterial Populations 422
Effects of Mismatch Repair on Adaptive Mutagenesis 423
Special Implications of Mismatch Repair Status for Pathogenic Bacteria 424
Mismatch Repair and Meiosis 424
Roles for Mismatch Repair Proteins in Gene Conversion and Antirecombination during
Meiosis 424
Roles for Mismatch Repair Proteins in Promoting Crossovers during Meiosis 424
Mismatch Repair Proteins and DNA Damage Recognition 427
Mismatch Repair Proteins and Alkylation Damage 427
Oxidative DNA Damage and Mismatch Repair 429
Cisplatin DNA Damage and Mismatch Repair 429
Mismatch Repair and Other Forms of DNA Damage 429
Roles of Mismatch Repair Proteins in Somatic Hypermutation and Class
Switch Recombination in the Immune Response 429
Somatic Hypermutation 430
Class Switch Recombination 430
Are the Effects of Mismatch Repair Proteins on Somatic Hypermutation and Class
Switch Recombination Direct or Indirect? 430
Mismatch Repair and Cadmium Toxicity 430
Specialized Mismatch Repair Systems 431
Very Short Patch Mismatch Correction in E. coli Corrects G T Mismatches Generated by
Deamination of 5 Methylcytosine 431
Correction of G T Mismatches Generated by Deamination of 5 Methylcytosine in
Eukaryotes 433
MutY Dependent Mismatch Repair 433
13 1 Repair of Mitochondrial DNA Damage 449
I Mitochondrial DNA 449
The Mitochondrial Genome 449
Mitochondrial Mutagenesis 449
DNA Damage in the Mitochondrial Genome 451
Mitochondrial DNA Repair 451
Reversal of Base Damage in Mitochondrial DNA 452
Mitochondrial Base Excision Repair 452
Monitoring Loss of Damage from Mitochondrial DNA 453
Removal of Oxidative Damage from Mitochondrial DNA 453
Enzymes for Base Excision Repair in Mitochondrial Extracts 454
Short Patch Base Excision Repair of Mitochondrial DNA 455
Age Related Studies of Mitochondrial DNA Repair 455
Alternative Excision Repair Pathway in Mitochondria? 456
Recombinational Repair in Mitochondrial DNA? 457
Summary 457
PART 3
DNA Damage Tolerance and Mutagenesis 461
14 I The SOS Responses of Prokaryotes to DNA Damage 463
1 The SOS Responses 463
Current Model for Transcriptional Control of the SOS Response 464
Physiological and Genetic Studies Indicate the Existence of the SOS
System 465
Induced Responses 465
Genetic Studies of recA and lexA 466
Essential Elements of SOS Transcriptional Regulation 469
Proteolytic Cleavage of X Repressor during SOS Induction 470
Induction of RecA Protein 471
LexA Protein Represses Both the recA+ and lexA+ Genes 471
LexA Protein Is Proteolytically Cleaved in a RecA Dependent Fashion 472
Mechanism of LexA Repressor Cleavage 473
Similarities between LexA, X Repressor, UmuD, and Signal Peptidase 476
Nature of the RecA Interactions Necessary for LexA, UmuD, and X Repressor
Cleavage 477
Identification of Genes in the SOS Network 478
Identifying SOS Genes by the Use of Fusions 478
Identifying SOS Genes by Searching for Potential LexA Binding Sites 479
Identifying SOS Genes by Expression Microarray Analysis 479
Generation of the SOS Inducing Signal In Vivo 481
Double Strand Breaks Are Processed by the RecBCD Nuclease/Helicase To Give Single
Stranded DNA Needed for SOS Induction 483
Generation of Single Stranded DNA by Bacteriophage, Plasmids, or Transposons Leads
to SOS Induction 483
An SOS Inducing Signal Is Generated when Cells Attempt To Replicate Damaged
DNA 484
Regions of Single Stranded DNA in Undamaged Cells 485
SOS Induction Caused by Mutations That Affect the Normal Processing of DNA 485
The Special Case of Phage ct 80 Induction 486
Modeling the SOS Signal 486
Additional Subtleties in the Transcriptional Regulation of the SOS
Responses 486
Strength and Location of SOS Boxes 486
DinI, RecX, and PsiB Proteins and isfA Affect SOS Regulation by Modulating RecA
Mediated Cleavage Reactions 488
Other Regulatory Systems Can Affect the Expression of SOS Regulated Genes 489
Physiological Considerations of the SOS Regulatory Circuit 489
Levels of Control of the SOS Response besides Transcriptional
Regulation 491
A Physiological Look at the SOS Responses 491
SOS Induced Responses That Promote Survival while Maintaining the Genetic Integrity
of the Genome 491
SOS Induced Responses That Promote Survival while Destabilizing the Genetic
Integrity of the Genome 492
SOS Induced Responses That Destabilize the Genetic Integrity of the Genome 493
SOS Induced Cell Cycle Checkpoints 495
Miscellaneous Physiological Effects of SOS Induction 495
SOS Responses in Pathogenesis and Toxicology 496
Relationships of the SOS Responses to Pathogenesis 496
Use of Fusions to SOS Genes To Detect Genotoxic Agents 497
SOS Responses in Other Bacteria 497
15 I Mutagenesis and Translesion Synthesis in Prokaryotes 509
I SOS Dependent Mutagenesis: Requirements for Particular Gene
Products 510
SOS Mutagenesis by UV Radiation and Most Chemicals Is Not a Passive Process 510
UmuD and UmuC Proteins Are Important for UV Radiation and Chemical
Mutagenesis 511
Multiple Levels of Post Translational Regulation of UmuD Protein: New Dimensions to
SOS Regulation 514
Inferences about the Mechanism of SOS Mutagenesis Based on Mutational
Spectra and Site Directed Adduct Studies 523
The Original lad System: a Purely Genetic Means of Determining Mutational
Spectra 523
Mutational Spectra Obtained by Direct DNA Sequencing 524
Factors Influencing the Mutational Spectrum for a Given Mutagen 524
Influence of Transcription Coupled Excision Repair on Mutational Spectra 525
Identification of Premutagenic Lesions 525
More Complex Lesions as Premutagenic Lesions 532
SOS Mutator Effect 534
The Road to Discovering the Molecular Mechanism of SOS Mutagenesis 535
A Further Requirement for RecA Protein in SOS Mutagenesis besides Facilitating LexA
and UmuD Cleavage 535
DNA Polymerases I and II Are Not Required for SOS Mutagenesis 536
Evidence Relating DNA Polymerase III to SOS Mutagenesis 536
Influence of the "Two Step" Model for SOS Mutagenesis 537
Initial Efforts To Establish an In Vitro System for SOS Mutagenesis 537
UmuC Related Proteins Are Found in All Three Kingdoms of Life 538
dinB, umuDC, and mucAB Encode Members of the Y Family of Translesion DNA
Polymerases 539
Revl Catalyzes the Formation of Phosphodiester Bonds: Rad30 and Xeroderma
Pigmentosum Variant Protein Are DNA Polymerases 539
DinB Is a DNA Polymerase 539
umuDC Encodes a Translesion DNA Polymerase, DNA Pol V, That Requires Accessory
Proteins 540
mucAB Encodes a Translesion DNA Polymerase, DNA Pol Rl, That Requires Accessory
Proteins 542
The Structure of Family Y DNA Polymerases Accounts for Their Special Ability To Carry
Out Translesion Synthesis 543
Multiple SOS Induced DNA Polymerases Can Contribute to SOS Induced
Mutagenesis 543
Protein Protein Interactions That Control the Activities of the umuDC
and dinB Gene Products 543
RecA and SSB Interactions with DNA Pol V 545
Interactions of the p Sliding Clamp with DNA Polymerases V and IV 546
Interactions of UmuD and UmuD' with Components of DNA Polymerase III 548
How Is Polymerase Switching Controlled? 549
What Is the Biological Significance of SOS Mutagenesis and Translesion
Synthesis by Specialized DNA Polymerases? 551
Translesion DNA Polymerases Can Contribute to Fitness and Survival in Two
Ways 551
Action of Translesion DNA Polymerases in Stationary Phase, Aging, and Stressed
Bacteria 551
SOS Independent Mutagenesis 554
Lesions That Do Not Require Induction of SOS Functions To Be Mutagenic 554
The UVM (UV Modulation of UV Mutagenesis) Response 555
Mutagenesis Resulting from the Misincorporation of Damaged Nucleotides 555
16 Recombinational Repair, Replication Fork Repair, and DNA
Damage Tolerance 569
DNA Damage Can Interfere with the Progress of Replication Forks and Lead
to the Generation of Various Structures 570
Formal Considerations 570
The In Vivo Situation Is More Complicated 571
Transient Partial Inhibition of DNA Replication after DNA Damage 573
Various DNA Structures Resulting Directly or Indirectly from DNA Damage
Can Be Processed by Homologous Recombination Proteins 574
RecA Protein: a Protein with Mechanistic Roles in Homologous Recombination and
DNA Repair 574
Other Key Proteins with Roles in Homologous Recombination 579
Recombinational Repair of Double Strand Breaks in E. coli 584
Model for Damage Tolerance Involving the Recombinational Repair of
Daughter Strand Gaps 586
Evidence Supporting the Model for Recombinational Repair of Daughter Strand
Gaps 586
Perspectives on Daughter Strand Gap Repair 590
An Error Free Process(es) Involving Recombination Functions Predominates over
Mutagenic Translesion Replication in a Model In Vivo System 592
Homologous Recombination Functions Play Critical Roles in the Stabilization
and Recovery of Arrested or Collapsed Replication Forks 593
Recognition of Fundamental Relationships between Replication and
Recombination 593
Possible Mechanisms for Regressing Replication Forks 598
Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks
Arrested by a Lesion Affecting Only One Strand of the DNA Template 599
Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks
Arrested by a Lesion or Blocks Affecting Both Strands of the DNA Template 602
Recovery of DNA Replication after DNA Damage: "Inducible Replisome
Reactivation/Replication Restart" 603
Polymerases Participating in Inducible Replisome Reactivation/Replication Restart
Revisited 603
17 DNA Damage Tolerance and Mutagenesis in Eukaryotic Cells 613
Phenomenology of UV Radiation Induced Mutagenesis in the Yeast
Saccharomyces cerevisiae 613
Insights from Mutational Spectra: the SUP4 0 System 613
Studies with Photoproducts at Defined Sites 615
Untargeted Mutagenesis in S. cerevisiae Cells Exposed to UV Radiation 616
Timing and Regulation of UV Radiation Induced Mutagenesis 616
Phenomenology of UV Radiation Induced Mutagenesis in Mammalian
Cells 617
DNA Replication in UV Irradiated Cells 617
Inducibility of Mutagenic Processes in Mammalian Cells? 621
Mutational Specificity of UV Radiation Induced Lesions 622
Summary and Conclusions 629
Molecular Mechanisms of Eukaryotic DNA Damage Tolerance and
Mutagenesis 629
Genetic Framework in S. cerevisiae 629
DNA Polymerase £ 629
Revl Protein 631
DNA Polymerase r\ 632
Other Vertebrate Lesion Bypass Polymerases 636
Handling of DNA Lesions by Bypass Polymerases: Synopsis and Comparison with In
Vivo Data 638
Somatic Hypermutation 639
The RAD6 Epistasis Group Dissected: Denning Error Prone and Error Free Tolerance
Mechanisms 642
Role of PCNA in Orchestrating the Choice of Damage Tolerance Pathways 647
Summary and Conclusions 649
18 1 Managing DNA Strand Breaks in Eukaryotic Cells: Repair
I Pathway Overview and Homologous Recombination 663
Overview of Various Pathways for Double Strand Break Repair in
Eukaryotes 663
Saccharomyces cerevisiae as a Model System for Detecting Double Strand Breaks
and Their Repair 665
Experimental Systems To Study Responses to Localized DNA Double Strand
Breaks 668
The HO Endonuclease System 668
Generation of Double Strand Breaks in Conditional Dicentric Chromosomes 668
I Scel Induced Targeted Double Strand Breaks 669
Homologous Recombination 671
End Processing as the Initiating Step 671
Pairing and Exchanging of Homologous DNA: Rad51, Its Orthologs, Paralogs, and
Interacting Partners 671
Role of Cohesin Proteins 681
The BRCA/Fanconi Pathway 682
Holliday Structure Resolution 685
Synthesis Dependent Strand Annealing and Break Induced
Replication 687
Single Strand Annealing 688
Transcription and Recombination 689
UV Radiation Stimulated Recombination 690
Repair of DNA Interstrand Cross Links 690
Interstrand Cross Link Repair in E. coli 691
Interstrand Cross Link Repair in S. cerevisiae 692
Interstrand Cross Link Repair in Higher Eukaryotes 695
Summary 696
19 | Managing DNA Strand Breaks in Eukaryotic Cells:
I Nonhomologous End Joining and Other Pathways 711
Nonhomologous End Joining 711
Introduction 711
V(D)J Recombination 712
Class Switch Recombination 714
Roles of the Ku Proteins 715
DNA Dependent Protein Kinase 718
Artemis: a Human SCID Syndrome Reveals a Player in Nonhomologous End
Joining 721
Ligation Step of Nonhomologous End Joining 722
Synopsis: Model for Vertebrate Nonhomologous End Joining 724
TheMrell Rad50 NBSl/Xrs2 Complex 724
Yeast Rad50, Mrel 1, and Xrs2 Function in Double Strand Break Repair and Meiosis
but Are Not Essential for Homologous Recombination 725
Two MRN Complex Components Are Associated with Human Genomic Instability
Syndromes 726
Null Mutations of MRN Components Are Lethal in Mammalian Cells, and
Hypomorphic Mutations Result in Severe Developmental Consequences 726
Focus Formation of the MRN Complex at Sites of Double Strand Breaks 727
In Vitro DNA Processing Activities of the MRN Complex 727
The MRN Complex in Nonhomologous DNA End Joining: a Major Role in 5. cerevisiae
but Possibly Not in Vertebrates 728
Role of the MRN Complex in Homologous Recombination 730
Significance of Nuclease Activity 731
Special Roles of the MRN Complex in Replication and Telomere Maintenance 731
"Molecular Velcro" and Beyond: Models for MRN Action Based on Structural
Analysis 733
Conclusions 734
Histone Modifications and Double Strand Breaks 735
Histone Phosphorylation 735
Histone Acetylation 736
Regulation of Pathway Choice 736
Repair of Single Strand Breaks 737
Sources and Significance of Single Strand Breaks 737
Poly(ADP Ribose) Polymerase as a Nick Sensor 738
XRCC1 Is a Scaffold Protein Orchestrating Interactions among Multiple Single Strand
Break Repair Proteins 738
PART 4
Regulatory Responses to DNA Damage in Eukaryotes 751
20 I Cell Cycle Checkpoints: General Introduction and Mechanisms of
1 DNA Damage Sensing 753
Cell Cycle Basics and the Emergence of the Checkpoint Concept 753
Studying Checkpoints 757
DNA Damage Sensing 758
Defining Checkpoint Triggering Damage and Sensor Proteins 758
The ATM Protein as a Damage Sensor 760
ATR Protein and Its Targeting Subunit 762
PCNA and RFC Like Clamp and Clamp Loader Complexes 764
Cross Talk between Sensors 765
The MRN Complex Plays an Additional Role in Checkpoint Arrests 766
Synopsis: Independent but Communicating Sensors Are Brought Together by Common
Requirements 767
Other Sensor Candidates 768
Sensing UV Radiation Damage 768
Damage Sensing in S Phase 769
211 Cell Cycle Checkpoints: Signal Transmission and Effector
I Targets 779
Generation and Transmission of a Checkpoint Activating Signal 779
The Rad53Sc/CdslSp/CHK2Hs Kinase 779
Mediators Are Important for Activation of Rad53Sc/CdslSp/CHK2Hs through DNA
Structure Sensors 781
Possible Mammalian Rad9Sc Homologs 782
S Phase Specific Activation of Rad53Sc/CdslSp/CHK2Hs 783
Chkl Kinase: Different Roles in Different Organisms 783
Activation of Chkl Kinase in 5. pombe, X. lams, and Humans 784
Summary: Pathways of Generating a Transmittable Damage Signal 784
Downstream Targets and Mechanisms That Regulate Cell Cycle
Progression 785
p53 as a Target of DNA Checkpoint Pathways 785
DNA Damage Induced G,/S Arrest 791
Modulation of S Phase in the Presence of DNA Damage 794
DNA Damage Induced G2/M Arrest 798
DNA Damage and the Regulation of M Phase 801
Synopsis 802
Effector Targets That Modulate DNA Repair 802
Repair Targets in Yeasts 802
Repair Targets in Mammalian Cells 803
Other Regulatory Responses to DNA Damage 803
Summary 804
22 I Transcriptional Responses to DNA Damage 817
I Introduction 817
Phenotypic Characterization of Pathway Inducibility 817
Analysis of Individual Genes 817
Differential Screening 818
Screens of Genome Arrays 818
Saccharomyces cerevisiae Genes Regulated in Response to DNA Damaging
Agents 818
Regulation of Ribonucleotide Reductase 818
Inducibility of Genes Involved in DNA Repair and Damage Tolerance: a Look at Various
Pathways 820
Genome Wide Approaches 823
Synopsis: No Satisfying Answer to the Question of Significance 827
Vertebrate Genes Regulated in Response to DNA Damaging Agents 828
Overview 828
p53 as a Transcription Factor 828
E2F Transcription Factor Family 830
Mammalian UV Radiation Response 831
Transcriptional Response to Ionizing Radiation 835
Summary and Conclusions 837
23 1 DNA Damage and the Regulation of Cell Fate 845
1 Adaptation and Cell Cycle Restart 846
Damage Signaling and Adaptation in Saccharomyces cerevisiae 846
Adaptation and Cell Cycle Restart by Silencing of Downstream Effectors 847
Recovery in Multicellular Eukaryotes 847
Regulation of Apoptosis 848
Introduction to Apoptotic Pathways 848
Activation of the Apoptosis Pathway by DNA Damage: the Roles of p53 Revisited 850
Role of DNA Damage Sensors and Transducers in Apoptosis 852
Additional Elements of DNA Damage Induced Apoptosis 853
Senescence, Cancer, and the DNA Damage Connection 854
Checkpoints and Cancer Therapy 856
PART 5
Disease States Associated with Defective Biological
Responses to DNA Damage 863
24 I Xeroderma Pigmentosum: a Disease Associated with Defective
i Nucleotide Excision Repair or Defective Translesion DNA
Synthesis 865
A Huge Literature on Xeroderma Pigmentosum 865
Primary Clinical Features 866
Other Clinical Features 867
Incidence and Demographics 867
Skin Cancer Associated with Xeroderma Pigmentosum 868
Phenotypes of Xeroderma Pigmentosum Cells 868
Chromosomal Abnormalities 868
Sensitivity to Killing by DNA Damaging Agents 869
Hypermutability 869
Source of Mutations 869
Defective Nucleotide Excision Repair 870
Repair of Oxidative Damage and Its Relationship to Neurological Disorders in
Xeroderma Pigmentosum 872
Defective Repair of Purine Cyclodeoxynucleosides 873
Genetic Complexity of Xeroderma Pigmentosum 874
The Xeroderma Pigmentosum Heterozygous State 875
Molecular Pathology 875
Xeroderma Pigmentosum from Genetic Complementation Group A 875
Xeroderma Pigmentosum from Genetic Complementation Group B 876
Xeroderma Pigmentosum from Genetic Complementation Group C 877
Xeroderma Pigmentosum from Genetic Complementation Group D 878
Xeroderma Pigmentosum from Genetic Complementation Group E 880
Mutations Have Only Been Found in the DDB2 Gene in XP E Group Cells 880
Xeroderma Pigmentosum from Genetic Complementation Group F 880
Xeroderma Pigmentosum from Genetic Complementation Group G 881
Summary 881
Unexplained Features of Xeroderma Pigmentosum 881
Cancer in Other Organs in Xeroderma Pigmentosum Individuals 881
Cancer Risk Assessment 882
Pathogenesis of Neurological Complications 882
Therapy 882
Mouse Models of Defective Nucleotide Excision Repair 882
Mice Defective in the Xpa Gene 883
Mice Defective in the Xpc Gene 884
Mice Defective in the Xpd Gene 886
Mice Defective in the Xpe Gene 886
Mice Defective in the Xpf Gene 887
Mice Defective in the Xpg Gene 887
Mice Defective in the Erccl Gene 887
Mice Defective in the Rad23A and Rad23B Genes 887
Summary 887
25 I Other Diseases Associated with Defects in Nucleotide Excision
I Repair of DNA 895
Cockayne Syndrome 895
Introduction 895
Clinical Phenotypes 895
Cellular Phenotypes 896
Genetics 898
Other Clinical Entities Associated with Mutations in Cockayne Syndrome or
XP Genes 905
Cerebro Oculo Facio Skeletal Syndrome 905
UV Sensitive Syndrome 905
Combined XP/CS Complex 906
Allelic Heterogeneity in Xeroderma Pigmentosum 906
Trichothiodystrophy 907
The "Transcription Syndrome" Hypothesis of XP/CS and Trichothiodystrophy 909
Direct Observations of Defective Transcription 910
Molecular Defects in XP/CS and Trichothiodystrophy Cells 910
Allele Specific and Gene Dosage Effects in This Group of Diseases 912
Skin Cancer in the Transcription Syndromes 913
Summary 913
26 I Diseases Associated with Defective Responses to DNA Strand
I Breaks 919
Ataxia Telangiectasia (Louis Bar Syndrome) 919
Clinical Features 919
Cellular Phenotypes 920
Identification of the Ataxia Telangiectasia Mutated (ATM) Gene 924
Aim Mutant Mice 926
Nijmegen Breakage Syndrome 928
Clinical Features 928
Cellular Characteristics 928
Identification of the Gene Mutated in Nijmegen Breakage Syndrome (NBS1) 929
Nihrin and Nijmegen Breakage Syndrome Cellular Phenotypes 929
Nbsl Mutant Mice 929
Genetic Heterogeneity 929
Heterozygosity and Cancer Predisposition 930
Ataxia Telangiectasia Like Disorder 930
DNA Ligase IV Mutations and Human Disease 930
Seckel Syndrome 930
Severe Combined Immunodeficiency 932
Clinical Features 933
Molecular Causes 934
Recombinase Activating Gene Deficiencies (RAG1 or Ry4G2 Deficient Severe Combined
Immunodeficiency) 935
Animal Models 935
Spinocerebellar Ataxia with Axonal Neuropathy 935
27 I Diseases Associated with Disordered DNA Helicase Function 947
i Biochemistry of RecQ Helicases 947
Crystal Structures of DNA Helicases 949
Fluorescence Resonance Energy Transfer 950
DNA Helicases That Participate in DNA Replication 952
RecQ Helicases and Human Disease 953
RecQ Helicases in Model Organisms 953
RecQ Protein in E. coli 953
Yeast Homologs of RecQ 954
Bloom Syndrome 954
Clinical Features of Bloom Syndrome Include a Marked Cancer Predisposition 955
Autosomal Recessive Genetics of Bloom Syndrome 955
Chromosome Instability as a Hallmark of Bloom Syndrome Cells 955
Bloom Syndrome Cells Exhibit Defects Associated with the S Phase of the Cell
Cycle 956
Bloom Syndrome Cells Manifest a Diversity of Subtle Defects in Enzymes Involved in
DNA Repair 957
Somatic Recombination Events in Bloom Syndrome Cells Facilitate Mapping and
Cloning of the BLM Gene 958
Interallelic Recombination and Its Potential Relevance to Bloom Syndrome 958
The BLM Gene Is a Member of the RecQ Family 958
Bloom Syndrome Heterozygotes May Be Predisposed to Cancer 959
The BLM Gene Product Is a RecQ Like Helicase 960
BLM Gene Expression 960
BLM Protein Localization 961
Modulation of Sister Chromatid Exchange 961
Association of BLM with Other DNA Repair Functions 962
Models for the Study of BLM Function 963
The Molecular Function of BLM Protein 964
Werner Syndrome 965
Clinical Features 965
Genetics 966
Cellular Phenotype of Werner Syndrome Cells 966
Identification of the WRN Gene 966
WRN Protein Contains DNA Helicase and Exonuclease Activities 967
WRN Protein Interactions 967
WRN Expression 968
WRN Protein Function 968
Mutations in RECQL4 Are Associated with Rothmund Thomson Syndrome
and RAPADILINO Syndrome 968
Clinical Features of Rothmund Thomson Syndrome 968
Cellular Characteristics of Rothmund Thomson Syndrome 968
Rothmund Thomson Syndrome Patients Have Mutations in RECQL4 969
RAPADILINO Syndrome 969
Summary of Human Diseases Associated with Defects in the RecQ Family of
DNA Helicase 971
28 I Additional Diseases Associated with Defective Responses to DNA
I Damage 979
Hereditary Nonpolyposis Colon Cancer 980
Clinical Presentation 980
Hereditary Nonpolyposis Colon Cancer and Microsatellite Instability 980
Hereditary Nonpolyposis Colon Cancer and Mismatch Repair 981
How Do Heterozygous Mutations Cause Cancer? 984
Mouse Models with Defects in Mismatch Repair Genes 985
Tumors in Homozygous Mutant Mice 985
Fanconi Anemia 986
Clinical Phenotypes 987
Genetics 988
Cellular Features 988
DNA Repair in Fanconi Anemia Cells 989
Genetic Complexity 989
Mouse Models 993
Final Comments 994
29 I Hereditary Diseases That Implicate Defective Responses to DNA
I Damage 1001
Hereditary Cancer Predisposition Syndromes 1001
Retinoblastoma 1004
Li Fraumeni Syndrome 1006
Breast Cancer Predisposition Syndromes 1007
Predisposition to Gastrointestinal Tumors 1008
Skin Cancer Syndromes 1016
Additional Cancer Predisposition Syndromes 1018
Disorders with Alterations in Chromatin Structure 1021
Immunodeficiency Centromeric Instability Facial Anomalies Syndrome 1021
Roberts Syndrome 1023
Alpha Thalassemia/Mental Retardation Syndrome, X Linked 1025
Rett Syndrome 1025
Rubinstein Taybi Syndrome 1026
Coffin Lowry Syndrome 1026
Saethre Chotzen Syndrome 1026
Dyskeratosis Congenita 1027
DNA Repair and Its Association with Aging 1028
Aging and the Age Related Decline in DNA Repair 1028
Reversal of Aging and DNA Repair 1030
Array Analysis of Aging in Mammals 1030
Engineered Mouse Models for Aging 1030
Telomeres and Aging 1031
Hutchinson Gilford Progeria Syndrome (Progeria) 1032
Down Syndrome (Trisomy 21) 1033
30 | DNA Polymorphisms in Gatekeeper and Guardian Genes 1049
I Human Genetic Variation 1050
DNA Structure/Repair Related Methodologies for Single Nucleotide
Polymorphism Detection 1052
Oligonucleotide Arrays 1052
Mismatch Repair Detection 1054
TDG/MutY Glycosylase Mismatch Detection 1054
MassEXTEND 1054
Stabilized Double D Loops 1054
Assessing the Role of DNA Repair Gene Polymorphisms in Disease 1056
Statistics and Population Based Studies 1056
Variability in DNA Repair Capacity 1057
Heterozygosity and DNA Repair Gene Mutations 1059
Heterozygosity for Genes Associated with Dominantly Inherited Disorders 1059
Heterozygosity for Genes Associated with Recessive Disorders 1061
Summarizing the Role of Heterozygosity 1061
DNA Repair Gene Polymorphisms 1062
DNA Repair Gene Single Nucleotide Polymorphism Discovery 1062
Polymorphisms That Impact the Levels of Chemical Induced DNA Damage 1062
Cytochrome P 450 Monooxygenase Gene 1062
Glutathione S Transferase Ml Gene 1063
iV Acetyltransferase 2 Gene 1063
DNA Repair Gene Polymorphisms and Putative Cancer Risk 1064
Pharmacogenomics and DNA Repair Gene Polymorphisms 1067
Polymorphic Alleles and Functional Defects 1067
Summary 1070
Appendix 1081
Table 1 Nomenclature of DNA repair genes 1081
Table 2 Human hereditary diseases and defective cellular responses to DNA
damage 1087
Index 1091 |
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| any_adam_object_boolean | 1 |
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| classification_tum | MED 570f BIO 220f BIO 750f CHE 860f BIO 180f BIO 450f |
| ctrlnum | (OCoLC)266071151 (DE-599)BVBBV021327888 |
| dewey-full | 572.86459 572.8/6459 |
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| dewey-sort | 3572.86459 |
| dewey-tens | 570 - Biology |
| discipline | Biologie Chemie Medizin |
| discipline_str_mv | Biologie Chemie Medizin |
| edition | 2. ed. |
| format | Book |
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| id | DE-604.BV021327888 |
| illustrated | Illustrated |
| index_date | 2024-07-02T14:00:47Z |
| indexdate | 2024-07-09T20:35:46Z |
| institution | BVB |
| isbn | 1555813194 |
| language | English |
| lccn | 2005045353 |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-014648207 |
| oclc_num | 266071151 |
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| physical | XXVII, 1118 S. Ill., graph. Darst. |
| publishDate | 2006 |
| publishDateSearch | 2006 |
| publishDateSort | 2006 |
| publisher | ASM Press |
| record_format | marc |
| spelling | DNA repair and mutagenesis Errol C. Friedberg ... 2. ed. Washington, DC ASM Press 2006 XXVII, 1118 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier ADN - Réparation DNA gtt Mutagenesis gtt Mutagenèse DNA repair Mutagenesis Mutagenese (DE-588)4170881-7 gnd rswk-swf DNS-Schädigung (DE-588)4150350-8 gnd rswk-swf DNS-Reparatur (DE-588)4150347-8 gnd rswk-swf DNS-Reparatur (DE-588)4150347-8 s Mutagenese (DE-588)4170881-7 s DE-604 DNS-Schädigung (DE-588)4150350-8 s Friedberg, Errol C. Sonstige oth 1. Auflage Friedberg, Errol C. DNA repair and mutagenesis HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=014648207&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | DNA repair and mutagenesis ADN - Réparation DNA gtt Mutagenesis gtt Mutagenèse DNA repair Mutagenesis Mutagenese (DE-588)4170881-7 gnd DNS-Schädigung (DE-588)4150350-8 gnd DNS-Reparatur (DE-588)4150347-8 gnd |
| subject_GND | (DE-588)4170881-7 (DE-588)4150350-8 (DE-588)4150347-8 |
| title | DNA repair and mutagenesis |
| title_auth | DNA repair and mutagenesis |
| title_exact_search | DNA repair and mutagenesis |
| title_exact_search_txtP | DNA repair and mutagenesis |
| title_full | DNA repair and mutagenesis Errol C. Friedberg ... |
| title_fullStr | DNA repair and mutagenesis Errol C. Friedberg ... |
| title_full_unstemmed | DNA repair and mutagenesis Errol C. Friedberg ... |
| title_old | Friedberg, Errol C. DNA repair and mutagenesis |
| title_short | DNA repair and mutagenesis |
| title_sort | dna repair and mutagenesis |
| topic | ADN - Réparation DNA gtt Mutagenesis gtt Mutagenèse DNA repair Mutagenesis Mutagenese (DE-588)4170881-7 gnd DNS-Schädigung (DE-588)4150350-8 gnd DNS-Reparatur (DE-588)4150347-8 gnd |
| topic_facet | ADN - Réparation DNA Mutagenesis Mutagenèse DNA repair Mutagenese DNS-Schädigung DNS-Reparatur |
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