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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
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