Khanna / Shiloh The DNA Damage Response: Implications on Cancer Formation and Treatment

1. Auflage 2009
ISBN: 978-90-481-2561-6
Verlag: Springer Netherlands
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 449 Seiten

The ?eld of cellular responses to DNA damage has attained widespread recognition and interest in recent years commensurate with its fundamental role in the ma- tenance of genomic stability. These responses, which are essential to preventing cellular death or malignant transformation, are organized into a sophisticated s- tem designated the “DNA damage response”. This system operates in all living organisms to maintain genomic stability in the face of constant attacks on the DNA from a variety of endogenous by-products of normal metabolism, as well as exogenous agents such as radiation and toxic chemicals in the environment. The response repairs DNA damage via an intricate cellular signal transduction network that coordinates with various processes such as regulation of DNA replication, tr- scriptional responses, and temporary cell cycle arrest to allow the repair to take place. Defects in this system result in severe genetic disorders involving tissue degeneration, sensitivity to speci?c damaging agents, immunode?ciency, genomic instability, cancer predisposition and premature aging. The ?nding that many of the crucial players involved in DNA damage response are structurally and functionally conserved in different species spurred discoveries of new players through similar analyses in yeast and mammals. We now understand the chain of events that leads to instantaneous activation of the massive cellular responses to DNA lesions. This book summarizes several new concepts in this rapidly evolving ?eld, and the advances in our understanding of the complex network of processes that respond to DNA damage.

Autoren/Hrsg.

Khanna, Kum Kum

Shiloh, Yosef

Inhaltsverzeichnis

1;Preface;4
2;Contents;6
3;Contributors;8
4;1 DNA Damage Sensing and Signaling;11
4.1;1.1 Preamble;11
4.2;1.2 DNA Damage Sensing and the Initiation of DNA Damage Signaling;13
4.3;1.3 ATM Signaling and the DNA Double-Strand Break Paradigm;14
4.3.1;1.3.1 ATM: The Master of DSB Signaling;15
4.3.2;1.3.2 ATM Activation by DSBs and MRN;16
4.3.3;1.3.3 Is ATM a DNA-Activated Kinase?;18
4.4;1.4 ATR Signaling: The Two-Man Rule;19
4.4.1;1.4.1 The Role of ssDNA in ATR Activation;19
4.4.2;1.4.2 The Role of 9-1-1 and TopBP1 in ATR Activation;20
4.5;1.5 Unresolved Questions;21
4.5.1;1.5.1 How is DNA Damage Sensed During DNA Damage Signaling?;21
4.5.2;1.5.2 How are PIKK Signaling Thresholds Established?;22
4.5.3;1.5.3 Does DNA-PKcs Play a Signaling Role?;22
4.5.4;1.5.4 Disassembly of DNA Damage Sensing Complexes;23
4.6;1.6 DNA Damage Signaling and Sensing: Clinical Perspectives;23
4.6.1;1.6.1 Biomarkers;23
4.6.2;1.6.2 DNA Damage Signaling Inhibitors;24
4.6.3;1.6.3 Suppressors of DNA Damage Signaling Defects;25
4.7;References;26
5;2 Signaling at Stalled Replication Forks;35
5.1;2.1 Introduction;35
5.2;2.2 Replication and Fork Stalling;35
5.2.1;2.2.1 Initiating DNA Replication;36
5.2.2;2.2.2 Replication Stress;36
5.3;2.3 ATR Signaling at a Stalled Replication Fork;38
5.3.1;2.3.1 ATRIP;39
5.3.2;2.3.2 The 9-1-1 Complex;41
5.3.3;2.3.3 TopBP1;42
5.3.4;2.3.4 CHK1;45
5.3.5;2.3.5 Regulation of DNA Replication by ATR;46
5.4;2.4 ATR Signaling and Cancer;47
5.5;2.5 Conclusions and Future Directions;48
5.6;References;49
6;3 An Oncogene-Induced DNA Replication Stress Model for Cancer Development;56
6.1;3.1 Introduction;56
6.2;3.2 Key Developments and Concepts;56
6.2.1;3.2.1 Identification of Oncogenes and Tumor Suppressors;57
6.2.2;3.2.2 Genomic Instability as a Characteristic of Most Human Cancers and Its Underlying Genetic Basis;57
6.2.3;3.2.3 Identification of a Pathway, Involving ARF and p53, by Which Oncogenes Induce Apoptosis or Senescence;59
6.3;3.3 A New Model to Explain Genomic Instability and Tumor Suppression in Human Cancers;59
6.3.1;3.3.1 Identification of DNA DSBs in Human Cancers and in Cells Expressing Activated Oncogenes;60
6.3.2;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
6.3.3;3.3.3 DNA Replication Stress Induces DNA DSBs and Genomic Instability in Cancer;62
6.4;3.4 A Model for Cancer Development;64
6.5;References;65
7;4 Cellular Responses to Oxidative Stress;73
7.1;4.1 Introduction;73
7.1.1;4.1.1 Cellular Redox State;73
7.1.2;4.1.2 Oxidative Stress;74
7.1.3;4.1.3 The Oxygen Molecule (O2);75
7.1.4;4.1.4 Oxygen Radicals;76
7.1.4.1;4.1.4.1 The Superoxide Anion Radical (-O2-);77
7.1.5;4.1.5 The Hydroxyl Radical (OH);77
7.1.6;4.1.6 The Peroxyl Radical (L);77
7.2;4.2 Non-Radical ROS;77
7.2.1;4.2.1 Hydrogen Peroxide (H2O2 );78
7.2.2;4.2.2 Nitric Oxide (NO) and Generation of the Peroxinitrite Anion (ONOO-);78
7.2.3;4.2.3 Cellular Defense Mechanisms Against Oxidative Stress;78
7.2.4;4.2.4 Brain Vulnerability to Oxidative Stress;81
7.2.5;4.2.5 Oxidative Stress in Neurodegenerative Diseases;81
7.3;4.3 Conclusions;83
7.4;References;84
8;5 Cell Cycle Regulation and DNA Damage;88
8.1;5.1 Introduction;88
8.2;5.2 Overview of the Cell Cycle;89
8.2.1;5.2.1 Cyclins and Cyclin-Dependent Kinases;91
8.2.2;5.2.2 Control of Cyclin Stability;92
8.2.3;5.2.3 Post-Translational Regulation of CDK Activity;92
8.2.4;5.2.4 Cell-Cycle Phase Transitions;93
8.2.4.1;5.2.4.1 G1/S-Phase;93
8.2.4.2;5.2.4.2 G2/M Transition;94
8.3;5.3 Cell Cycle Interfaces of the DNA Damage Response;95
8.3.1;5.3.1 G1/S Checkpoint;95
8.3.1.1;5.3.1.1 Rapid G1/S Checkpoint Arrest;96
8.3.1.2;5.3.1.2 Delayed G1/S Checkpoint Arrest and the p53 Tumor Suppressor;97
8.3.2;5.3.2 S-Phase DNA Damage Checkpoints;98
8.3.2.1;5.3.2.1 ATM-Dependent Intra-S-Phase Checkpoint;98
8.3.2.2;5.3.2.2 ATR-Dependent S-Phase Checkpoint Arrest;100
8.3.2.3;5.3.2.3 S/M Checkpoint;101
8.3.3;5.3.3 G2/M Checkpoint;102
8.3.3.1;5.3.3.1 Initiation of G2/M Arrest;102
8.3.3.2;5.3.3.2 Stress-Activated Kinases and G2/M Delay;104
8.3.3.3;5.3.3.3 Transcription-Dependent G2/M Checkpoint Pathways;105
8.3.3.4;5.3.3.4 Recovery from G2/M Checkpoint Arrest;105
8.4;5.4 The DDR and Cell Cycle Latency: The Special Case of Neurons;106
8.4.1;5.4.1 Concluding Remarks: Exploiting Checkpoint Defects Therapeutically;107
8.5;References;108
9;6 Chromatin Modifications Involved in the DNA Damage Response to Double Strand Breaks;115
9.1;6.1 Chromatin Structure;115
9.2;6.2 Overview of DSB Repair Pathways;116
9.3;6.3 Histone Modifications Associated with DNA Damage Repair;117
9.3.1;6.3.1 Phosphorylation of H2AX;117
9.3.2;6.3.2 Additional Histone Phosphorylation Events;119
9.4;6.4 Methylation of Histones;120
9.5;6.5 Ubiquitination of Histones;120
9.6;6.6 Histone Acetylation and Deacetylation;121
9.7;6.7 Recruitment of Chromatin Remodelling Factors;125
9.7.1;6.7.1 SWI/SNF;125
9.7.2;6.7.2 The INO80 Remodelling Complex;126
9.7.3;6.7.3 Remodels the Structure of Chromatin (RSC);127
9.7.4;6.7.4 Tip60/p400 and the NuA4 Complex;128
9.8;6.8 Recent Advances in the Chromatin-Repair Field;129
9.9;6.9 Conclusions;130
9.10;References;130
10;7 Telomere Metabolism and DNA Damage Response;138
10.1;7.1 Telomeres;138
10.2;7.2 Telomere Dysfunction;142
10.3;7.3 DNA Damage Foci at Dysfunctional Telomeres;143
10.4;7.4 Factors Common in DNA Damage Response and Telomere Metabolism;144
10.5;7.5 ATM;146
10.6;7.6 MDC1;148
10.7;7.7 c-Abl;148
10.8;7.8 Mammalian Rad9;148
10.9;7.9 DNA-PK;149
10.10;7.10 Ku;149
10.11;7.11 MRN;150
10.12;7.12 14-3-3;150
10.13;7.13 Heterochromatin Protein 1 (HP1);151
10.14;7.14 Chromatin Modification in Response to DNA DSBs;152
10.15;7.15 DSB Signaling and Checkpoint Activation;153
10.16;7.16 Conclusions and Future Prospects;153
10.17;References;154
11;8 DNA Double Strand Break Repair: Mechanisms and Therapeutic Potential;162
11.1;8.1 Introduction;163
11.2;8.2 Detection and Repair of IR-Induced DNA Damage;164
11.2.1;8.2.1 IR-Induced Forms of DNA Damage;164
11.2.2;8.2.2 The Major DSB Repair Pathways in Mammalian Cells;164
11.2.2.1;8.2.2.1 Non-Homologous End Joining (NHEJ);164
11.2.2.2;8.2.2.2 Alternative Non-Homologous End Joining (Alt-NHEJ);168
11.2.3;8.2.3 Homology Directed Repair (HDR);168
11.2.4;8.2.4 DSB Repair Pathway Choice;170
11.3;8.3 The Therapeutic Potential of DSB Repair Pathways;170
11.3.1;8.3.1 DSB Repair Pathways as Predictors of Radiation Response and Treatment Outcome;170
11.3.2;8.3.2 Small Molecule Inhibitors of DSB Repair Pathways;171
11.3.3;8.3.3 Synthetic Lethality;172
11.4;8.4 Summary;173
11.5;References;173
12;9 DNA Base Excision Repair: A Recipe for Survival;183
12.1;9.1 Introduction;185
12.2;9.2 DNA Damage;185
12.2.1;9.2.1 Endogenous DNA Lesions;186
12.2.2;9.2.2 Exogenous Lesions;186
12.2.2.1;9.2.2.1 Drugs and Other Alkylating Agents;186
12.3;9.3 Base Excision Repair (BER): A Pathway for Repairing Inappropriate Bases and Single-Strand Breaks: Early Observations;187
12.3.1;9.3.1 Further Clarification of the Base Excision Step;188
12.4;9.4 Distinct Catalytic Mechanisms of Mono and Bifunctional DNA Glycosylases;189
12.5;9.5 A Common Mechanism for Substrate Recognition by Mono and Bifunctional DNA-Glycosylases;190
12.6;9.6 Mechanism of Discrimination of Damaged from Normal Bases by DNA Glycosylases;190
12.7;9.7 Distinct Steps Following Base Excision by DNA Glycosylases: Repair of AP Sites and Single-Strand Interruption with Nonligatable Termini;191
12.7.1;9.7.1 AP-Endonuclease (APE), a Ubiquitous Repair Protein with Dual Nucleolytic Activities;191
12.7.2;9.7.2 Mammalian Cells Express Only Xth type APE, APE1;192
12.7.3;9.7.3 Additional APE's Identified in Mammals;192
12.7.4;9.7.4 Additional Complexities: Involvement of PNK in a BER Subpathway for Mammalian Cells;193
12.8;9.8 Repair of Alkylated Bases by Monofunctional DNA Glycosylases and by MGMT, an Unusual Suicide Protein;193
12.9;9.9 Distal Steps in BER;194
12.10;9.10 Complexity of BER in Mammalian Cells: SN- vs. LP-BER;194
12.11;9.11 Repair Interactome A New Paradigm in BER;196
12.12;9.12 Coordination of Reaction Steps in the BER Pathway;197
12.13;9.13 Essentiality and Biological Consequences of BER Deficiency;198
12.13.1;9.13.1 Nonessentiality of Individual DNA Glycosylases in Mammals;198
12.13.2;9.13.2 APE1 is Essential in Mammalian Cells;199
12.13.3;9.13.3 Accumulation of Single-Strand Breaks in the Genome of APE1-Null Cells;200
12.14;9.14 BER in Mitochondria;200
12.15;9.15 Regulation of BER Activity In Vivo in Response to Genotoxic Stress;201
12.15.1;9.15.1 Sumoylation of TDG;201
12.15.2;9.15.2 Acetylation of DNA Glycosylases;202
12.16;9.16 Synopsis and Future Perspective;202
12.17;References;203
13;10 DNA Damage Tolerance and Translesion Synthesis;213
13.1;10.1 Introduction;213
13.2;10.2 In the Wilderness Pre 1999;214
13.3;10.3 1999 Light at the End of the Tunnel Y Family Polymerases Discovered;215
13.4;10.4 Structures of Y-Family Polymerases;216
13.5;10.5 Functions of Polymerases in TLS;216
13.5.1;10.5.1 Pol ;216
13.5.2;10.5.2 Pol ;219
13.5.3;10.5.3 Pol ;219
13.5.4;10.5.4 Rev1 and pol;220
13.6;10.6 Localisation and Protein-Protein Interactions of TLS Polymerases;221
13.7;10.7 Polymerase Switching;223
13.7.1;10.7.1 Ubiquitination of PCNA;223
13.7.2;10.7.2 Rad18 and Rad5;224
13.8;10.8 Events at Stalled Forks;228
13.9;10.9 Concluding Remarks;229
13.10;References;229
14;11 Nucleotide Excision Repair: from DNA Damage Processing to Human Disease;239
14.1;11.1 Introduction;239
14.2;11.2 Global Genome Repair;240
14.2.1;11.2.1 DNA Lesion Recognition in GG-NER;241
14.2.2;11.2.2 Assembly of the Preincision Complex;242
14.2.3;11.2.3 Dual Incision Step;244
14.2.4;11.2.4 The Post-Incision Step in NER;245
14.2.5;11.2.5 Damage Signaling in NER;246
14.2.6;11.2.6 Chromatin Structure and NER;248
14.3;11.3 Transcription Coupled Repair;250
14.3.1;11.3.1 Molecular Models for TC-NER;251
14.4;11.4 NER Deficiencies and Cancer;253
14.5;11.5 Perspectives;255
14.6;References;256
15;12 Chromosomal Single-Strand Break Repair;264
15.1;12.1 The Source and Structure of Endogenous DNA Single-Strand Breakage;264
15.2;12.2 DNA Single-Strand Breaks and Cell Fate;265
15.3;12.3 Mechanisms of Chromosomal Single-Strand Break Repair (SSBR);266
15.3.1;12.3.1 Detection of SSBs;266
15.3.2;12.3.2 DNA End Processing;269
15.3.3;12.3.3 DNA Gap Filling;270
15.3.4;12.3.4 DNA Ligation;271
15.4;12.4 The Organisation of SSBR;272
15.5;12.5 SSBR and the Cell Cycle;272
15.6;12.6 SSBR and Hereditary Genetic Disease;274
15.6.1;12.6.1 Ataxia with Oculomotor Apraxia Type-1 (AOA1);274
15.6.2;12.6.2 Spinocerebellar Ataxia with Axonal Neuropathy-1 (SCAN-1);276
15.7;12.7 Do SSBs and/or DSBs Cause SCAN1 and AOA1?;276
15.8;12.8 SSBs and Cancer;277
15.9;12.9 SSBs and Neurodegeneration;277
15.10;References;278
16;13 Mouse Models of DNA Double Strand Break Repair Deficiency and Cancer;288
16.1;13.1 Overview;288
16.2;13.2 Introduction;288
16.3;13.3 DNA DSB Repair Pathways;290
16.4;13.4 Mouse Models of DSBR Deficiency and Tumorigenesis;291
16.4.1;13.4.1 Inactivation of Homologous Recombination in the Mouse;292
16.4.2;13.4.2 Inactivation of Non-Homologous End-Joining in the Mouse;296
16.4.3;13.4.3 Inactivation of the DNA Damage Response;298
16.5;13.5 Conclusions and Perspectives;300
16.6;References;300
17;14 Cancer Biomarkers Associated with Damage Response Genes;309
17.1;14.1 Introduction;309
17.2;14.2 The Cellular Damage Response;310
17.3;14.3 Definitions of Prognostic and Predictive Factors;311
17.4;14.4 Biological Samples for Biomarker Measurements: Technical Considerations;312
17.5;14.5 Measurement of Biomarkers at the Protein Level;313
17.5.1;14.5.1 Protein Expression by Immunohistochemistry;313
17.5.2;14.5.2 Protein Expression in Serum and Plasma;318
17.6;14.6 Measurement of Biomarkers at the mRNA Level;319
17.7;14.7 Measurement of Biomarkers at the DNA Level;321
17.7.1;14.7.1 DNA Adducts and Measurements of Oxidative Stress;321
17.7.2;14.7.2 Germline Mutations as Biomarkers;322
17.7.3;14.7.3 Detection of Circulating Free Mutant DNA (ctDNA);323
17.7.4;14.7.4 Gene Promoter Methylation as a Predictive Factor;324
17.7.5;14.7.5 Single Nucleotide Polymorphisms and Genome Wide Association Studies: Cancer Risk and Pharmacogenetics;324
17.8;14.8 Conclusions;327
17.9;References;328
18;15 Linking Human RecQ Helicases to DNA Damage Response and Aging;333
18.1;15.1 Introduction: Genome Instability Syndromes and Aging;333
18.2;15.2 Human RecQ Helicases and DNA Double Strand Break Response;336
18.3;15.3 Human RecQ Helicases and DNA Replication Stress;338
18.4;15.4 Mouse Models Associated with RecQ Helicase Deficiency;340
18.5;15.5 Other RecQ Helicases;341
18.6;15.6 Perspectives;343
18.7;References;343
19;16 Single-Stranded DNA Binding Proteins Involved in Genome Maintenance;350
19.1;16.1 Single Stranded DNA;350
19.2;16.2 Evolution of SSBs;351
19.3;16.3 Structural Organisation;351
19.4;16.4 E.coli SSB;352
19.5;16.5 An Introduction to Replication Protein A;353
19.6;16.6 RPA Structure and DNA Binding;354
19.7;16.7 RPA Interacting Proteins;354
19.8;16.8 Phosphorylation of RPA;356
19.9;16.9 RPA and the Link with HDR Repair;357
19.10;16.10 hSSB1 and hSSB2;359
19.11;16.11 SSBs as Drug Targets;360
19.12;16.12 Summary;360
19.13;References;361
20;17 The Fanconi anemia-BRCA Pathway and Cancer;368
20.1;17.1 Introduction;368
20.2;17.2 Fanconi anemia;369
20.3;17.3 The Fanconi anemia-BRCA Pathway;373
20.3.1;17.3.1 The Fanconi anemia Genes;373
20.3.2;17.3.2 The FA Core Complex;378
20.3.3;17.3.3 Monoubiquitination of FANCD2 and FANCI;380
20.3.4;17.3.4 Activation of the FA-BRCA Pathway;380
20.3.5;17.3.5 Deubiquitination of FANCD2 by USP1;383
20.3.6;17.3.6 Localization of FA Proteins in Chromatin;384
20.3.7;17.3.7 Interaction of FA Proteins and Non-FA Proteins Involved in DNA Repair and DNA Damage Response;385
20.4;17.4 Cellular Defects in FA;386
20.4.1;17.4.1 Homologous Recombination;386
20.4.2;17.4.2 Translesion Synthesis ;388
20.4.3;17.4.3 Function of FA Proteins in Intra S Phase Cell Cycle Checkpoints;389
20.4.4;17.4.4 Notch-HES1 Pathway and the FA Core Complex;390
20.4.5;17.4.5 Other Functions of FA Proteins and Other Proteins Interacting with FA Proteins;390
20.5;17.5 FA Animal Models;391
20.5.1;17.5.1 Mouse Models;391
20.5.2;17.5.2 Other Models;391
20.6;17.6 The FA-BRCA Pathway in Human Cancer in the General (Non-FA) Population;392
20.6.1;17.6.1 FANCF Methylation in Ovarian Cancer;392
20.6.2;17.6.2 FANCF Methylation in Other Tumors;396
20.6.3;17.6.3 Other FA Genes;397
20.7;17.7 Implication of the FA-BRCA Pathway in Cancer Therapy;398
20.7.1;17.7.1 Exploiting the Defects of the FA-BRCA Pathway in Cancer Cells;398
20.7.2;17.7.2 Functional Restoration of the FA-BRCA Pathway as a Mechanism of Acquired Drug Resistance;399
20.7.3;17.7.3 The FA-BRCA Pathway as a Drug Target;400
20.8;17.8 Concluding Remarks;400
20.9;References;401
21;18 BRCA1 and BRCA2: Role in the DNA Damage Response, Cancer Formation and Treatment;416
21.1;18.1 Introduction;416
21.2;18.2 BRCA1 Structure and Function;417
21.2.1;18.2.1 BRCA1 and DNA Repair;419
21.2.2;18.2.2 BRCA1, DNA Damage Signaling and Cell Cycle Arrest;420
21.2.3;18.2.3 BRCA1 Ubiquitination and the DNA Damage Response;425
21.2.4;18.2.4 BRCA1 and Transcriptional Regulation;427
21.3;18.3 BRCA2 Structure and Function;429
21.3.1;18.3.1 BRCA2 and Cell Cycle Regulation;431
21.3.2;18.3.2 BRCA2 Chromatin Remodeling and Transcriptional Regulation;432
21.4;18.4 Tissue Specificity of BRCA1 and BRCA2 Related Cancers;433
21.5;18.5 BRCA1, BRCA2 and Cancer Treatment;433
21.6;18.6 Conclusion;437
21.7;References;437
22;Index;445