Cellular Response to the Genotoxic Insult The Question of Threshold for Genotoxic Carcinogens

Contents......Page 8
1. Introduction......Page 16
2. Background......Page 17
3. Studies in Rodents to Evaluate Low Dose Effects of Genotoxic Carcinogens......Page 18
4.1 Previous Conclusions......Page 21
4.2 Metabolic Inactivation of Genotoxic Compounds......Page 22
4.3 Key Events in the Transformation of a Cell......Page 23
5.1 DNA Repair......Page 25
5.2 Post-translational Regulation......Page 27
5.4 Apoptosis......Page 28
6. Conclusions......Page 29
References......Page 32
1. Threshold Effects Observed in Experimental Studies......Page 36
1.1.1 Introduction......Page 38
1.1.2 Genetic Alterations and Cancer......Page 39
1.1.3 Carcinogenic Process......Page 40
1.1.4 Key Events for Mutagenic Mode of Action......Page 41
1.1.5 Mechanism of Induction of Chromosomal and Gene Mutations......Page 42
1.1.6 Mutation Induction and ‘Hit Theory’......Page 43
1.1.7 Next Steps......Page 44
Acknowledgements......Page 45
References......Page 46
1.2.1 Introduction......Page 48
1.2.2 Dose-effect Studies of Initiation of Liver Carcinogenesis......Page 50
1.2.3 Conclusions......Page 56
1.2.4 Human Relevance......Page 57
References......Page 60
1.3.1 Introduction......Page 67
1.3.2 Material and Methods......Page 69
1.3.3 Results......Page 70
1.3.4 Discussion......Page 72
1.3.5 Conclusion......Page 75
References......Page 76
2. Metabolic Inactivation of Genotoxic Reactants......Page 78
2.1.1 Introduction......Page 80
2.1.2 Discussion of Individual Compounds......Page 81
2.1.3 Oxidative Stress Leading to Secondary Genotoxicity......Page 91
References......Page 98
2.2.1 Biotransformation......Page 107
References......Page 123
3. DNA Repair......Page 128
3.1.1 Introduction......Page 130
3.1.2.1 Types of Oxidative DNA Lesions......Page 131
3.1.2.2 Consequences of Unrepaired Oxidative DNA Damages......Page 133
3.1.3.1 The Base Excision Repair (BER) Pathway......Page 137
3.1.3.2 The DNA Glycosylases......Page 139
3.1.3.3 DNA Glycosylase Biology......Page 141
3.1.4.1 APE, Polb, LigIIIa-XRCC1......Page 144
3.1.4.2 Biology of the Downstream Enzymes......Page 146
3.1.5 Is there a Threshold for the Consequences of Oxidative DNA Damages?......Page 148
3.1.6 Conclusions......Page 149
References......Page 150
3.2.1 Introduction......Page 175
3.2.3.1 Homologous Recombination and Non-homologous End Joining......Page 176
3.2.3.2 Nucleotide Excision Repair......Page 178
3.2.3.3 Base Excision Repair......Page 180
3.2.4 DNA Damage Signalling......Page 181
3.2.4.2 DNA Damage Response in Adult Stem Cells......Page 182
3.2.4.3 DNA Damage Response in Post-mitotic Cells......Page 183
3.2.5.1 Apoptosis......Page 184
3.2.5.2 Autophagy......Page 185
3.2.6 Conclusions......Page 186
References......Page 189
3.3.1 Base Excision Repair......Page 195
3.3.2 BER Regulation......Page 197
3.3.3 ARF in Cancer......Page 198
3.3.4 ARF Protein Structure, Stability and Expression......Page 199
3.3.5 ARF Roles in the Cellular Response to DNA Damage......Page 200
3.3.6 Conclusions and Future Prospective......Page 201
References......Page 202
3.4.1 Introduction......Page 205
3.4.2.1 Direct Reversal of Damage......Page 206
3.4.2.2 Excision Repair Pathways......Page 207
3.4.2.3 Repair of Clustered Damage on both DNA Strands......Page 209
3.4.2.4 Tolerance of Persisting Damage by Translesion DNA Synthesis......Page 210
3.4.3 Overlap between DNA Damage Processing Pathways......Page 211
3.4.4 Regulation of Damage Recognition for Nucleotide Excision Repair......Page 212
3.4.5 Hereditary Diseases in which DNA Damage Processing is Defective......Page 214
3.4.5.2 Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS)......Page 215
3.4.5.4 Ataxia Telangiectasia (AT)......Page 216
3.4.5.6 Other Diseases Involving Deficient Processing of DNA......Page 217
3.4.6 Conclusions Relevant to Threshold Effects for Genotoxic Carcinogens......Page 218
References......Page 220
4. Apoptosis......Page 228
4.1.1 Introduction......Page 230
4.1.2 The DNA Damage Response......Page 231
4.1.4 Detection of Blocked DNA Replication Forks......Page 232
4.1.5 Phosphorylation of Histone 2AX......Page 233
4.1.6 Signaling to Cell Cycle Checkpoints......Page 234
4.1.7 Survival Strategy: DSB Repair......Page 235
4.1.9 Survival Signaling Mediated by NF-kB......Page 237
4.1.10 Survival Signaling Mediated by Akt......Page 238
4.1.11 Death Strategy: Apoptosis......Page 239
4.1.11.2 Sustained JNK and p38 Kinase Activation......Page 241
4.1.12 Death Strategy: Necrosis......Page 242
References......Page 244
4.2.1 Introduction......Page 254
4.2.2.1 ATM/ATR Activation and Kinase Cascade......Page 255
4.2.2.2 Key Role of p53 in Genotoxic Stress Response......Page 257
4.2.3 Cell Senescence in Response to DNA Damage......Page 258
4.2.3.1 Molecular Pathways of DNA Damage-Induced Senescence......Page 259
4.2.3.2 Cellular Senescence—Dead End Or?......Page 260
4.2.4 Apoptosis as a Fast-acting Response to DNA Damage......Page 261
4.2.4.1 Multiple Functions of p53 in DNA Damage-Induced Apoptosis......Page 262
4.2.4.2 p53-independent Response to DNA Damage......Page 263
4.2.4.3 Role of Caspase-2 in DNA Damage Responses......Page 264
4.2.5 Cell Death by Mitotic Catastrophe......Page 265
4.2.6 DNA Damage and Autophagy......Page 267
4.2.6.1 Autophagic Cell Death Induced by DNA Damage......Page 268
4.2.6.2 Controversial Role of Autophagy in Mechanisms of Cell Survival or Death......Page 269
4.2.6.3 Switch between Autophagic and Apoptotic Pathways......Page 270
4.2.7.1 PARP-mediated Necrosis......Page 271
4.2.7.2 Cleavage of PARP and Connection with p53......Page 272
4.2.7.3 AIF-mediated Programmed Necrosis......Page 273
Acknowledgements......Page 274
References......Page 275
4.3.1 Introduction......Page 281
4.3.3 Transcription-blocking Agents......Page 282
4.3.3.1 Genotoxic Agents......Page 284
4.3.3.2 Chemotherapeutic Agents......Page 286
4.3.3.3 Mechanisms of Action of Commonly Used Transcription Inhibitors......Page 288
4.3.4 The Transcription Stress Response......Page 289
4.3.5 Post-transcriptional Effects......Page 290
4.3.6 Induction of Apoptosis by Transcription-blocking DNA lesions......Page 291
4.3.6.2 Role of p53......Page 292
4.3.6.4 Tug-of-war between Replication and Blocked Transcription Factories......Page 293
4.3.7 Transcription Inhibition and Aging......Page 294
References......Page 295
5. Epigenetic Mechanisms......Page 306
5.1.1 Introduction......Page 308
5.1.2 Gap Junctional Intercellular Communication: Basic Concepts......Page 309
5.1.3 Epigenetic Determinants of Gap Junctional Intercellular Communication......Page 311
5.1.4 Gap Junctional Intercellular Communication as a Target for Epigenetic Carcinogens......Page 316
5.1.5 Conclusions and Perspectives......Page 318
References......Page 319
Subject Index......Page 327