The DNA Damage Response: Implications on Cancer Formation and Treatment (eBook)

Preface 4
Contents 6
Contributors 8
1 DNA Damage Sensing and Signaling 11
1.1 Preamble 11
1.2 DNA Damage Sensing and the Initiation of DNA Damage Signaling 13
1.3 ATM Signaling and the DNA Double-Strand Break Paradigm 14
1.3.1 ATM: The Master of DSB Signaling 15
1.3.2 ATM Activation by DSBs and MRN 16
1.3.3 Is ATM a DNA-Activated Kinase? 18
1.4 ATR Signaling: The Two-Man Rule 19
1.4.1 The Role of ssDNA in ATR Activation 19
1.4.2 The Role of 9-1-1 and TopBP1 in ATR Activation 20
1.5 Unresolved Questions 21
1.5.1 How is DNA Damage Sensed During DNA Damage Signaling? 21
1.5.2 How are PIKK Signaling Thresholds Established? 22
1.5.3 Does DNA-PKcs Play a Signaling Role? 22
1.5.4 Disassembly of DNA Damage Sensing Complexes 23
1.6 DNA Damage Signaling and Sensing: Clinical Perspectives 23
1.6.1 Biomarkers 23
1.6.2 DNA Damage Signaling Inhibitors 24
1.6.3 Suppressors of DNA Damage Signaling Defects 25
References 26
2 Signaling at Stalled Replication Forks 35
2.1 Introduction 35
2.2 Replication and Fork Stalling 35
2.2.1 Initiating DNA Replication 36
2.2.2 Replication Stress 36
2.3 ATR Signaling at a Stalled Replication Fork 38
2.3.1 ATRIP 39
2.3.2 The 9-1-1 Complex 41
2.3.3 TopBP1 42
2.3.4 CHK1 45
2.3.5 Regulation of DNA Replication by ATR 46
2.4 ATR Signaling and Cancer 47
2.5 Conclusions and Future Directions 48
References 49
3 An Oncogene-Induced DNA Replication Stress Model for Cancer Development 56
3.1 Introduction 56
3.2 Key Developments and Concepts 56
3.2.1 Identification of Oncogenes and Tumor Suppressors 57
3.2.2 Genomic Instability as a Characteristic of Most Human Cancers and Its Underlying Genetic Basis 57
3.2.3 Identification of a Pathway, Involving ARF and p53, by Which Oncogenes Induce Apoptosis or Senescence 59
3.3 A New Model to Explain Genomic Instability and Tumor Suppression in Human Cancers 59
3.3.1 Identification of DNA DSBs in Human Cancers and in Cells Expressing Activated Oncogenes 60
3.3.2 The DNA Damage Checkpoint as an Important Mediator of Oncogene-Induced Senescence and/or Apoptosis and a Barrier to Tumor Development 61
3.3.3 DNA Replication Stress Induces DNA DSBs and Genomic Instability in Cancer 62
3.4 A Model for Cancer Development 64
References 65
4 Cellular Responses to Oxidative Stress 73
4.1 Introduction 73
4.1.1 Cellular Redox State 73
4.1.2 Oxidative Stress 74
4.1.3 The Oxygen Molecule (O2) 75
4.1.4 Oxygen Radicals 76
4.1.4.1 The Superoxide Anion Radical (-O2-) 77
4.1.5 The Hydroxyl Radical (OH) 77
4.1.6 The Peroxyl Radical (L) 77
4.2 Non-Radical ROS 77
4.2.1 Hydrogen Peroxide (H2O2 ) 78
4.2.2 Nitric Oxide (NO) and Generation of the Peroxinitrite Anion (ONOO-) 78
4.2.3 Cellular Defense Mechanisms Against Oxidative Stress 78
4.2.4 Brain Vulnerability to Oxidative Stress 81
4.2.5 Oxidative Stress in Neurodegenerative Diseases 81
4.3 Conclusions 83
References 84
5 Cell Cycle Regulation and DNA Damage 88
5.1 Introduction 88
5.2 Overview of the Cell Cycle 89
5.2.1 Cyclins and Cyclin-Dependent Kinases 91
5.2.2 Control of Cyclin Stability 92
5.2.3 Post-Translational Regulation of CDK Activity 92
5.2.4 Cell-Cycle Phase Transitions 93
5.2.4.1 G1/S-Phase 93
5.2.4.2 G2/M Transition 94
5.3 Cell Cycle Interfaces of the DNA Damage Response 95
5.3.1 G1/S Checkpoint 95
5.3.1.1 Rapid G1/S Checkpoint Arrest 96
5.3.1.2 Delayed G1/S Checkpoint Arrest and the p53 Tumor Suppressor 97
5.3.2 S-Phase DNA Damage Checkpoints 98
5.3.2.1 ATM-Dependent Intra-S-Phase Checkpoint 98
5.3.2.2 ATR-Dependent S-Phase Checkpoint Arrest 100
5.3.2.3 S/M Checkpoint 101
5.3.3 G2/M Checkpoint 102
5.3.3.1 Initiation of G2/M Arrest 102
5.3.3.2 Stress-Activated Kinases and G2/M Delay 104
5.3.3.3 Transcription-Dependent G2/M Checkpoint Pathways 105
5.3.3.4 Recovery from G2/M Checkpoint Arrest 105
5.4 The DDR and Cell Cycle Latency: The Special Case of Neurons 106
5.4.1 Concluding Remarks: Exploiting Checkpoint Defects Therapeutically 107
References 108
6 Chromatin Modifications Involved in the DNA Damage Response to Double Strand Breaks 115
6.1 Chromatin Structure 115
6.2 Overview of DSB Repair Pathways 116
6.3 Histone Modifications Associated with DNA Damage Repair 117
6.3.1 Phosphorylation of H2AX 117
6.3.2 Additional Histone Phosphorylation Events 119
6.4 Methylation of Histones 120
6.5 Ubiquitination of Histones 120
6.6 Histone Acetylation and Deacetylation 121
6.7 Recruitment of Chromatin Remodelling Factors 125
6.7.1 SWI/SNF 125
6.7.2 The INO80 Remodelling Complex 126
6.7.3 Remodels the Structure of Chromatin (RSC) 127
6.7.4 Tip60/p400 and the NuA4 Complex 128
6.8 Recent Advances in the Chromatin-Repair Field 129
6.9 Conclusions 130
References 130
7 Telomere Metabolism and DNA Damage Response 138
7.1 Telomeres 138
7.2 Telomere Dysfunction 142
7.3 DNA Damage Foci at Dysfunctional Telomeres 143
7.4 Factors Common in DNA Damage Response and Telomere Metabolism 144
7.5 ATM 146
7.6 MDC1 148
7.7 c-Abl 148
7.8 Mammalian Rad9 148
7.9 DNA-PK 149
7.10 Ku 149
7.11 MRN 150
7.12 14-3-3 150
7.13 Heterochromatin Protein 1 (HP1) 151
7.14 Chromatin Modification in Response to DNA DSBs 152
7.15 DSB Signaling and Checkpoint Activation 153
7.16 Conclusions and Future Prospects 153
References 154
8 DNA Double Strand Break Repair: Mechanisms and Therapeutic Potential 162
8.1 Introduction 163
8.2 Detection and Repair of IR-Induced DNA Damage 164
8.2.1 IR-Induced Forms of DNA Damage 164
8.2.2 The Major DSB Repair Pathways in Mammalian Cells 164
8.2.2.1 Non-Homologous End Joining (NHEJ) 164
8.2.2.2 Alternative Non-Homologous End Joining (Alt-NHEJ) 168
8.2.3 Homology Directed Repair (HDR) 168
8.2.4 DSB Repair Pathway Choice 170
8.3 The Therapeutic Potential of DSB Repair Pathways 170
8.3.1 DSB Repair Pathways as Predictors of Radiation Response and Treatment Outcome 170
8.3.2 Small Molecule Inhibitors of DSB Repair Pathways 171
8.3.3 Synthetic Lethality 172
8.4 Summary 173
References 173
9 DNA Base Excision Repair: A Recipe for Survival 183
9.1 Introduction 185
9.2 DNA Damage 185
9.2.1 Endogenous DNA Lesions 186
9.2.2 Exogenous Lesions 186
9.2.2.1 Drugs and Other Alkylating Agents 186
9.3 Base Excision Repair (BER): A Pathway for Repairing Inappropriate Bases and Single-Strand Breaks: Early Observations 187
9.3.1 Further Clarification of the Base Excision Step 188
9.4 Distinct Catalytic Mechanisms of Mono and Bifunctional DNA Glycosylases 189
9.5 A Common Mechanism for Substrate Recognition by Mono and Bifunctional DNA-Glycosylases 190
9.6 Mechanism of Discrimination of Damaged from Normal Bases by DNA Glycosylases 190
9.7 Distinct Steps Following Base Excision by DNA Glycosylases: Repair of AP Sites and Single-Strand Interruption with Nonligatable Termini 191
9.7.1 AP-Endonuclease (APE), a Ubiquitous Repair Protein with Dual Nucleolytic Activities 191
9.7.2 Mammalian Cells Express Only Xth type APE, APE1 192
9.7.3 Additional APE's Identified in Mammals 192
9.7.4 Additional Complexities: Involvement of PNK in a BER Subpathway for Mammalian Cells 193
9.8 Repair of Alkylated Bases by Monofunctional DNA Glycosylases and by MGMT, an Unusual Suicide Protein 193
9.9 Distal Steps in BER 194
9.10 Complexity of BER in Mammalian Cells: SN- vs. LP-BER 194
9.11 Repair Interactome A New Paradigm in BER 196
9.12 Coordination of Reaction Steps in the BER Pathway 197
9.13 Essentiality and Biological Consequences of BER Deficiency 198
9.13.1 Nonessentiality of Individual DNA Glycosylases in Mammals 198
9.13.2 APE1 is Essential in Mammalian Cells 199
9.13.3 Accumulation of Single-Strand Breaks in the Genome of APE1-Null Cells 200
9.14 BER in Mitochondria 200
9.15 Regulation of BER Activity In Vivo in Response to Genotoxic Stress 201
9.15.1 Sumoylation of TDG 201
9.15.2 Acetylation of DNA Glycosylases 202
9.16 Synopsis and Future Perspective 202
References 203
10 DNA Damage Tolerance and Translesion Synthesis 213
10.1 Introduction 213
10.2 In the Wilderness Pre 1999 214
10.3 1999 Light at the End of the Tunnel Y Family Polymerases Discovered 215
10.4 Structures of Y-Family Polymerases 216
10.5 Functions of Polymerases in TLS 216
10.5.1 Pol 216
10.5.2 Pol 219
10.5.3 Pol 219
10.5.4 Rev1 and pol 220
10.6 Localisation and Protein-Protein Interactions of TLS Polymerases 221
10.7 Polymerase Switching 223
10.7.1 Ubiquitination of PCNA 223
10.7.2 Rad18 and Rad5 224
10.8 Events at Stalled Forks 228
10.9 Concluding Remarks 229
References 229
11 Nucleotide Excision Repair: from DNA Damage Processing to Human Disease 239
11.1 Introduction 239
11.2 Global Genome Repair 240
11.2.1 DNA Lesion Recognition in GG-NER 241
11.2.2 Assembly of the Preincision Complex 242
11.2.3 Dual Incision Step 244
11.2.4 The Post-Incision Step in NER 245
11.2.5 Damage Signaling in NER 246
11.2.6 Chromatin Structure and NER 248
11.3 Transcription Coupled Repair 250
11.3.1 Molecular Models for TC-NER 251
11.4 NER Deficiencies and Cancer 253
11.5 Perspectives 255
References 256
12 Chromosomal Single-Strand Break Repair 264
12.1 The Source and Structure of Endogenous DNA Single-Strand Breakage 264
12.2 DNA Single-Strand Breaks and Cell Fate 265
12.3 Mechanisms of Chromosomal Single-Strand Break Repair (SSBR) 266
12.3.1 Detection of SSBs 266
12.3.2 DNA End Processing 269
12.3.3 DNA Gap Filling 270
12.3.4 DNA Ligation 271
12.4 The Organisation of SSBR 272
12.5 SSBR and the Cell Cycle 272
12.6 SSBR and Hereditary Genetic Disease 274
12.6.1 Ataxia with Oculomotor Apraxia Type-1 (AOA1) 274
12.6.2 Spinocerebellar Ataxia with Axonal Neuropathy-1 (SCAN-1) 276
12.7 Do SSBs and/or DSBs Cause SCAN1 and AOA1? 276
12.8 SSBs and Cancer 277
12.9 SSBs and Neurodegeneration 277
References 278
13 Mouse Models of DNA Double Strand Break Repair Deficiency and Cancer 288
13.1 Overview 288
13.2 Introduction 288
13.3 DNA DSB Repair Pathways 290
13.4 Mouse Models of DSBR Deficiency and Tumorigenesis 291
13.4.1 Inactivation of Homologous Recombination in the Mouse 292
13.4.2 Inactivation of Non-Homologous End-Joining in the Mouse 296
13.4.3 Inactivation of the DNA Damage Response 298
13.5 Conclusions and Perspectives 300
References 300
14 Cancer Biomarkers Associated with Damage Response Genes 309
14.1 Introduction 309
14.2 The Cellular Damage Response 310
14.3 Definitions of Prognostic and Predictive Factors 311
14.4 Biological Samples for Biomarker Measurements: Technical Considerations 312
14.5 Measurement of Biomarkers at the Protein Level 313
14.5.1 Protein Expression by Immunohistochemistry 313
14.5.2 Protein Expression in Serum and Plasma 318
14.6 Measurement of Biomarkers at the mRNA Level 319
14.7 Measurement of Biomarkers at the DNA Level 321
14.7.1 DNA Adducts and Measurements of Oxidative Stress 321
14.7.2 Germline Mutations as Biomarkers 322
14.7.3 Detection of Circulating Free Mutant DNA (ctDNA) 323
14.7.4 Gene Promoter Methylation as a Predictive Factor 324
14.7.5 Single Nucleotide Polymorphisms and Genome Wide Association Studies: Cancer Risk and Pharmacogenetics 324
14.8 Conclusions 327
References 328
15 Linking Human RecQ Helicases to DNA Damage Response and Aging 333
15.1 Introduction: Genome Instability Syndromes and Aging 333
15.2 Human RecQ Helicases and DNA Double Strand Break Response 336
15.3 Human RecQ Helicases and DNA Replication Stress 338
15.4 Mouse Models Associated with RecQ Helicase Deficiency 340
15.5 Other RecQ Helicases 341
15.6 Perspectives 343
References 343
16 Single-Stranded DNA Binding Proteins Involved in Genome Maintenance 350
16.1 Single Stranded DNA 350
16.2 Evolution of SSBs 351
16.3 Structural Organisation 351
16.4 E.coli SSB 352
16.5 An Introduction to Replication Protein A 353
16.6 RPA Structure and DNA Binding 354
16.7 RPA Interacting Proteins 354
16.8 Phosphorylation of RPA 356
16.9 RPA and the Link with HDR Repair 357
16.10 hSSB1 and hSSB2 359
16.11 SSBs as Drug Targets 360
16.12 Summary 360
References 361
17 The Fanconi anemia-BRCA Pathway and Cancer 368
17.1 Introduction 368
17.2 Fanconi anemia 369
17.3 The Fanconi anemia-BRCA Pathway 373
17.3.1 The Fanconi anemia Genes 373
17.3.2 The FA Core Complex 378
17.3.3 Monoubiquitination of FANCD2 and FANCI 380
17.3.4 Activation of the FA-BRCA Pathway 380
17.3.5 Deubiquitination of FANCD2 by USP1 383
17.3.6 Localization of FA Proteins in Chromatin 384
17.3.7 Interaction of FA Proteins and Non-FA Proteins Involved in DNA Repair and DNA Damage Response 385
17.4 Cellular Defects in FA 386
17.4.1 Homologous Recombination 386
17.4.2 Translesion Synthesis 388
17.4.3 Function of FA Proteins in Intra S Phase Cell Cycle Checkpoints 389
17.4.4 Notch-HES1 Pathway and the FA Core Complex 390
17.4.5 Other Functions of FA Proteins and Other Proteins Interacting with FA Proteins 390
17.5 FA Animal Models 391
17.5.1 Mouse Models 391
17.5.2 Other Models 391
17.6 The FA-BRCA Pathway in Human Cancer in the General (Non-FA) Population 392
17.6.1 FANCF Methylation in Ovarian Cancer 392
17.6.2 FANCF Methylation in Other Tumors 396
17.6.3 Other FA Genes 397
17.7 Implication of the FA-BRCA Pathway in Cancer Therapy 398
17.7.1 Exploiting the Defects of the FA-BRCA Pathway in Cancer Cells 398
17.7.2 Functional Restoration of the FA-BRCA Pathway as a Mechanism of Acquired Drug Resistance 399
17.7.3 The FA-BRCA Pathway as a Drug Target 400
17.8 Concluding Remarks 400
References 401
18 BRCA1 and BRCA2: Role in the DNA Damage Response, Cancer Formation and Treatment 416
18.1 Introduction 416
18.2 BRCA1 Structure and Function 417
18.2.1 BRCA1 and DNA Repair 419
18.2.2 BRCA1, DNA Damage Signaling and Cell Cycle Arrest 420
18.2.3 BRCA1 Ubiquitination and the DNA Damage Response 425
18.2.4 BRCA1 and Transcriptional Regulation 427
18.3 BRCA2 Structure and Function 429
18.3.1 BRCA2 and Cell Cycle Regulation 431
18.3.2 BRCA2 Chromatin Remodeling and Transcriptional Regulation 432
18.4 Tissue Specificity of BRCA1 and BRCA2 Related Cancers 433
18.5 BRCA1, BRCA2 and Cancer Treatment 433
18.6 Conclusion 437
References 437
Index 445