DNA Damage Recognition

Front cover......Page 1
Preface......Page 6
Contents......Page 8
Contributors......Page 20
Part I Mechanisms of Damage Recognition: Theoretical Considerations......Page 26
1. INTRODUCTION......Page 28
2. ROLE OF DNA FLEXIBILITY IN SEQUENCE-DEPENDENT ACTIVITY OF UDG......Page 29
3. OPENING AND BENDING DYNAMICS OF G
U MISMATCHES IN DNA......Page 33
4. CONCLUSIONS......Page 38
REFERENCES......Page 40
2. MECHANISM FOR AN INCREASED RATE OF TARGET SITE LOCATION......Page 46
3. IN VITRO EVIDENCE FOR PROCESSIVE NICKING ACTIVITY OF DNA GLYCOSYLASES 3.1. Bacteriophage T4 Pyrimidine Dimer Glycosylase......Page 48
3.2. Other DNA Glycosylases......Page 50
4. DISCOVERY AND SIGNIFICANCE OF IN VIVO PROCESSIVE NICKING ACTIVITY BY T4-PDG 4.1. In Vivo Evidence for Processive Incision and Repair of UV Irradiated DNAs......Page 51
5. DNA BENDING AS A POTENTIAL PREREQUISITE FOR NUCLEOTIDE FLIPPING......Page 52
6. MECHANISMS OF NUCLEOTIDE FLIPPING 6.1. Flipping of a Single Nucleotide......Page 54
7. SPECIFICITY OF GLYCOSYLASE BINDING SITES AND CATALYTIC ACTIVITIES......Page 55
REFERENCES......Page 56
1. INTRODUCTION......Page 58
2. DNA LESION RECOGNITION AND REMOVAL......Page 61
2.2. Post-Translational Modification of DNA Glycosylases......Page 63
Table 2......Page 65
2.3. Bi-functional Glycosylases......Page 66
3. STRAND INCISION......Page 67
4. GAP FILLING AND RELIGATION......Page 71
4.1. Protein Interactions with pol-b in Short-Patch BER......Page 72
4.2. Protein Interactions with pol-b in Long-Patch BER......Page 73
5. XRCC1 COORDINATION......Page 74
5.1. DNA Damage Recognition......Page 75
5.2. XRCC1 Scaffold Coordination......Page 76
6.1. Protein Interactions......Page 77
6.2. Post-Translational Modifications......Page 78
8. CONCLUSIONS......Page 79
REFERENCES......Page 80
Part II UV Damage and Other Bulky DNA-Adducts......Page 90
1.1. DNA Photochemistry......Page 92
1.2. Primary Photoproducts......Page 93
2. CYCLOBUTANE PYRIMIDINE DIMERS......Page 94
2.2. Tautomerization......Page 95
2.3. Deamination of C-Containing CPDs......Page 98
2.4. Tertiary Structure of Cis–Syn Cyclobutane Dimer-Containing DNA......Page 99
2.5. Base Pairing and Thermodynamic Properties......Page 103
3. OTHER DIMER-RELATED PRODUCTS 3.1. Dimers with a Cleaved Intradimer Phosphodiester Backbone......Page 104
3.2. Non-Adjacent Dimers......Page 105
4. (6–4) PRODUCTS......Page 106
4.1. Tertiary Structure of (6–4)-Containing DNA......Page 107
4.2. Base Pairing and Thermodynamic Properties of (6–4)-Containing DNA......Page 108
5.1. Tertiary Structure of Dewar-Containing DNA......Page 111
5.3. Thio Analogs of (6–4) and Dewar Products......Page 112
6. SPORE PHOTOPRODUCT......Page 113
7. TA+ PRODUCT......Page 114
REFERENCES......Page 115
1. OVERVIEW OF PHOTOLYASES......Page 120
2. THE NATURE OF THE SUBSTRATES......Page 121
3. CHARACTERIZATION OF SUBSTRATE BINDING AND DISCRIMINATION BY PHOTOLYASES 3.1. CPD Photolyases......Page 122
4. INTERACTIONS AT THE PHOTOLYASE–PHOTOPRODUCT INTERFACE: THE MOLECULAR BASIS FOR SUBSTRATE BINDING AND DISCRIMINATION......Page 123
4.1. Contacts on DNA......Page 124
4.2. Structure of CPD Photolyases and a Model for DNA Binding......Page 126
4.3. Substrate Discrimination......Page 128
5.2. Photoreactivation in Actively Transcribed Genes......Page 130
5.3. Photoreactivation at Replication Origins, Promoters, and Telomeres......Page 131
REFERENCES......Page 132
1.1. Overview of Nucleotide Excision Repair......Page 136
2. DIVERSITY OF DNA LESIONS RECOGNIZED......Page 138
3.1. UvrA Protein Motifs......Page 139
3.2. UvrB Protein Structure......Page 142
3.3. UvrC Protein Structure......Page 145
4.1. Dimerization of UvrA......Page 148
4.2. DNA Damage Detection by UvrA......Page 149
4.3. Damage Verification by the UvrA2B Complex......Page 151
5. DNA DAMAGE RECOGNITION WITHIN THE BIOLOGICAL CONTEXT OF THE CELL......Page 155
REFERENCES......Page 158
2. NUCLEOTIDE EXCISION REPAIR SUBSTRATES......Page 164
3. EUKARYOTIC NER REACTION......Page 165
4. SUBUNITS OF THE EUKARYOTIC NER MACHINERY......Page 167
5. STEPWISE ASSEMBLY OF THE MAMMALIAN NER RECOGNITION COMPLEX......Page 168
6. A PREASSEMBLED REPAIROSOME IN YEAST?......Page 169
7. ROLE OF DAMAGED DNA BINDING IN DAMAGE RECOGNITION......Page 171
8. RECOGNITION OF BULKY LESIONS DURING TRANSCRIPTION-COUPLED DNA REPAIR......Page 172
9. BIPARTITE SUBSTRATE DISCRIMINATION IN THE GGR PATHWAY......Page 173
10. XPC–hHR23B AS A SENSOR OF DEFECTIVE BASE PAIRING......Page 174
11. TRANSCRIPTION FACTOR IIH AS A SENSOR OF DEFECTIVE DEOXYRIBONUCLEOTIDE CHEMISTRY......Page 176
12. ROLE OF XPA–RPA IN INTEGRATING DIFFERENT RECOGNITION SIGNALS......Page 178
14. REGULATION OF THE DAMAGE RECOGNITION PROCESS......Page 180
15. CONCLUSIONS......Page 183
REFERENCES......Page 184
1.1. Transcription......Page 190
1.2. Transcription-Coupled Repair......Page 192
2. THE BEHAVIOR OF RNA POLYMERASE COMPLEXES WITH DIFFERENT TYPES OF DNA DAMAGE......Page 193
3. THE BEHAVIOR OF RNA POLYMERASE COMPLEXES AT LESIONS AND NER......Page 195
3.2. TCR and NER......Page 196
4.1. Alkylation Damage......Page 198
4.2. Oxidative Damage......Page 199
REFERENCES......Page 200
1. INTRODUCTION......Page 206
2. HETEROGENEITY OF DNA REPAIR 2.1. Effects of DNA Structure on DNA Repair......Page 207
2.2. Effect of Transcription on DNA Repair......Page 209
3.2. Quantification at the Sequence Level......Page 210
4. DNA REPAIR IN TRANSCRIPTIONALLY ACTIVE GENES IN DIFFERENT ORGANISMS 4.1. Rodent Cells......Page 213
4.2. Human Cells......Page 214
4.3. Escherichia coli cells......Page 216
4.4. Yeast......Page 217
5. MODELS OF TCR IN EUKARYOTIC CELLS......Page 218
6. EFFECT OF DIFFERENT KINDS OF DNA DAMAGE ON TCR......Page 219
REFERENCES......Page 220
1. INTRODUCTION......Page 226
2. NUCLEOSOMES: HETEROGENEITY IN A CONSERVED STRUCTURE......Page 227
3. DYNAMIC PROPERTIES OF NUCLEOSOMES REGULATE DNA ACCESSIBILITY......Page 228
4. DAMAGE TOLERANCE OF NUCLEOSOMES......Page 233
5. REPAIR OF NUCLEOSOMES BY PHOTOLYASE......Page 234
6. REPAIR OF NUCLEOSOMES BY NER......Page 236
8. CHROMATIN REMODELING AND DNA REPAIR......Page 239
REFERENCES......Page 241
1. INTRODUCTION......Page 248
2.2. Biochemical Characterization of S. pombe UVDE......Page 249
3. RECOGNITION AND PROCESSING OF UV PHOTOPRODUCTS......Page 251
5. RECOGNITION AND PROCESSING OF ABASIC SITES......Page 252
6. MODIFIED BASES NOT RECOGNIZED BY UVDE......Page 254
7. RECOGNITION AND PROCESSING OF BASE–BASE MISMATCHES......Page 255
8. RECOGNITION AND PROCESSING OF INSERTION–DELETION LOOPS......Page 256
9. SUBSEQUENT STEPS FOLLOWING UVDE-INITIATED ALTERNATIVE EXCISION REPAIR......Page 257
10. SCHIZOSACCHAROMYCES POMBE UVDE HOMOLOGS......Page 258
REFERENCES......Page 259
2. INTRODUCTION......Page 264
3. STRUCTURAL CONSEQUENCES OF PLATINUM-BINDING TO DOUBLE-STRANDED DNA......Page 265
3.1. The 1,2-d(GpG) Intrastrand Cross-Link......Page 266
3.3. The Interstrand d(GpC)/d(G+pC) Cross-Link......Page 267
Table 1......Page 269
4. RECOGNITION OF cis-DDP-1,2 INTRASTRAND CROSS-LINK BY CELLULAR PROTEINS......Page 270
4.1. Chromatin Reorganization......Page 271
4.2. Transcription Factors......Page 275
4.3. Repair Proteins......Page 276
5. SUMMARY AND OUTLOOK......Page 279
REFERENCES......Page 280
1. INTRODUCTION......Page 288
2. METABOLISM OF PAH TO DIOL EPOXIDES AND FORMATION OF STEREOISOMERIC DNA ADDUCTS......Page 290
3.2. Computational Analysis of Adduct Structure by Molecular Dynamic (MD) Simulations and Molecular Mechanics Poisson– Boltzmann Surface Area (MM–PBSA) Methods......Page 292
4. PAH–DNA ADDUCTS: CONFORMATIONAL MOTIFS......Page 294
4.4. Adenine Adducts: Intercalation from the Major Groove......Page 296
4.5. Adenine Adducts: Distorting Intercalation from the Major Groove......Page 297
5. INSIGHTS INTO THE STRUCTURAL MOTIFS AT THE NUCLEOSIDE ADDUCT LEVEL DERIVED FROM COMPUTATIONAL APPROACHES......Page 298
6.1. Stereoisomeric Bay Region B[a]P-N+-dG Adducts......Page 299
6.2. Differences in the Processing of Bay Region Trans-B[a]P-N6-dA and Fjord B[c]Ph-N6-dA Adducts by NER Enzymes......Page 300
7.1. Overview......Page 301
7.2. Thermal Dissociation of PAH-Modified Duplexes: Correlation of......Page 302
8. COMPUTATIONAL ANALYSIS......Page 304
8.1. The Bay Region R and S Trans-B[a]P-N-dA Adducts......Page 305
8.2. The Fjord Region R and S Trans-B[c]Ph-N-dA Adducts......Page 310
8.3. NER of Other Bulky Fjord PAH-N6-dA Adducts......Page 312
8.4. Resistance of Fjord PAH-N-dA Adducts to NER and the Unusually High Tumorigenic Activities of Fjord PAH Compounds......Page 313
9.2. Relationships Between Adduct Properties and NER......Page 314
REFERENCES......Page 315
Part III Non-Bulky Base Damage......Page 322
1. THE BASE EXCISION REPAIR PATHWAY......Page 324
2. DNA GLYCOSYLASE STRUCTURAL FAMILIES......Page 325
2.1. The Helix–Hairpin–Helix Motif......Page 326
2.2. The Helix–Two Turn–Helix Motif......Page 327
3. SPECIFIC MECHANISMS FOR RECOGNITION OF DAMAGE 3.1. Oxidation Damage......Page 328
3.2. Deamination Products......Page 331
3.3. Alkylation Damage......Page 335
4.1. APE1......Page 338
4.2. Endo IV......Page 339
REFERENCES......Page 340
1. BIOLOGICAL CONSEQUENCES OF OXIDATIVE DAMAGE......Page 348
2. MAJOR REPAIR ENZYMES THAT RECOGNIZE OXIDATIVE BASE DAMAGE......Page 351
2.1. Endonuclease III......Page 352
2.2. Formamidopyrimidine N-glycosylase......Page 354
2.3. Endonuclease VIII......Page 357
3. REPAIR PATHWAYS FOR OXIDATIVE DNA DAMAGE 3.1. Base Excision Repair......Page 358
3.2. Role of Nucleotide Excision Repair in Oxidative DNA Damage Removal......Page 359
REFERENCES......Page 360
1.1. SN1 vs. SN2......Page 364
1.3. Bifunctional Alkylating Agents......Page 365
2. DNA REPAIR SYSTEMS FOR REMOVAL OF ALKYLATING AGENT DAMAGE......Page 366
3. O6-ALKYLGUANINE DNA METHYLTRANSFERASES—AGTS......Page 367
3.1. Procaryotic AGTs......Page 369
3.2. Eucaryotic AGTs......Page 374
4. AlkB—2-OXOGLUTARATE-DEPENDENT FE(II)-DEPENDENT OXYGENASES......Page 380
4.1 Procaryotic 2-Oxoglutarate-Dependent Fe(II)-Dependent Oxygenases......Page 381
4.2. Eucaryotic 2-Oxoglutarate-Dependent Fe(II)-Dependent Oxygenases......Page 384
5.1. 3-Methyladenine-DNA Glycosylases......Page 387
5.2. Thymine-DNA Glycosylases......Page 400
6. NUCLEOTIDE EXCISION REPAIR......Page 402
6.1. Procaryotic NER......Page 403
ABBREVIATIONS......Page 405
REFERENCES......Page 407
2. LESIONS AND THEIR CONSEQUENCES......Page 414
3. DEAMINATING AGENTS 3.1. Water......Page 415
3.2. Nitrosating Agents......Page 416
3.3. Other Agents......Page 417
4. ENDONUCLEASE V, AN ENZYME SPECIFIC FOR DEAMINATED PURINES......Page 418
5. HYPOXANTHINE/ALKYLPURINE DNA GLYCOSYLASES 5.1. Two Classes of Enzyme......Page 421
5.2. AlkA Protein (3-Methyladenine Glycosylase II) of E. coli......Page 422
5.3. Human Alkyladenine (Alkylpurine) Glycosylase (hAAG)......Page 423
REFERENCES......Page 424
1. INTRODUCTION......Page 428
2. OXIDIZED BASE-SPECIFIC GLYCOSYLASES IN E. COLI AND MAMMALS......Page 429
2.1. Discovery of Nei Orthologs in Mammalian Cells......Page 430
2.4. Distinct Requirements for NEIL-Initiated BER......Page 431
2.6. In Vivo Functions of NEIL1 and NEIL2......Page 433
2.7. Preference of NEIL1 and NEIL2 for Substrate Lesions in DNA Bubble Structures......Page 434
2.8. Affinity of NEIL1 and NEIL2 for Bubble Structure......Page 435
2.9. Potential Role of NEILs in Transcription and Replication-Associated Repair......Page 437
2.10. Role of NEILs in Transcription-Coupled Repair......Page 438
2.11. TCR of Oxidatively Damaged Bases in the Mammalian Genome......Page 439
2.12. Role of NEIL1 in Replication-Associated Repair......Page 440
3. CONCLUSIONS......Page 441
REFERENCES......Page 442
1. AP SITE FORMATION AND BIOLOGICAL IMPACT......Page 446
2. AP-DNA DYNAMICS AND STRUCTURE......Page 448
3. AP ENDONUCLEASES......Page 450
4.1. Endonuclease IV Family......Page 451
4.2. Exonuclease III Family......Page 453
5. AP SITE REPAIR IN GENERAL......Page 457
ACKNOWLEDGMENTS......Page 460
REFERENCES......Page 461
1. INTRODUCTION......Page 470
2.2. mtDNA Replication, Copy Number, and Organization......Page 471
2.3. Involvement of mtDNA Mutations in Human Disease......Page 473
3. OXIDATIVE mtDNA DAMAGE RESISTANCE AND REPAIR......Page 474
3.1. Resistance to Oxidative mtDNA Damage: Packaging, Copy Number, and Degradation......Page 475
3.2. Base Excision Repair of Oxidative mtDNA Damage......Page 476
4. NEW LESSONS ABOUT OXIDATIVE mtDNA DAMAGE FROM THE BUDDING YEAST, S. CEREVISIAE, GENETIC MODEL SYSTEM......Page 477
4.1. BER and Overlapping Oxidative mtDNA Damage Resistance Pathways......Page 478
4.3. Influence of Mitochondrial Function on Nuclear Genome Stability......Page 479
5. CONCLUSIONS AND NEW HORIZONS......Page 480
REFERENCES......Page 481
Part IV Mismatch Repair......Page 486
1.1. Introduction to the Mechanism—The Bacterial Paradigm......Page 488
1.2. The Eukaryotic MutS and MutL Homologues......Page 490
2.2. Mode of Mismatch Binding and Recognition by MutS Proteins......Page 491
2.4. Function of MutL—A Second Switch in Mismatch Repair......Page 493
3. MECHANISM OF MISMATCH REPAIR 3.1. The Static Trans-Activation Model......Page 494
3.2. The Hydrolysis-Dependent Translocation Model......Page 495
3.4. Downstream Effectors in MMR......Page 496
3.5. The MMR-Replication Conundrum......Page 498
4. IMPLICATIONS......Page 499
REFERENCES......Page 500
1. INTRODUCTION......Page 508
2. STRUCTURE OF Vsr......Page 510
2.1. Biochemistry of Vsr......Page 513
2.2. Interaction Between MMR and VSP Repair......Page 514
REFERENCES......Page 515
Part V Replication and Bypass of DNA Lesions......Page 518
1. INTRODUCTION......Page 520
2. TRANSLESION DNA SYNTHESIS AND THE SOS RESPONSE......Page 521
4. FIDELITY OF POL V......Page 522
5. LESION BYPASS BY POL V......Page 523
6. ACCESSORY PROTEINS ARE REQUIRED FOR LESION BYPASS BY POL V......Page 524
7. OTHER DNA POLYMERASES INVOLVED IN TLS IN E. COLI......Page 526
8. IN VIVO ROLE OF TLS......Page 527
REFERENCES......Page 528
1. INTRODUCTION......Page 532
2. CONCEPTS OF TRANSLESION SYNTHESIS......Page 534
3.1. Polf......Page 535
3.2. The Y Family of DNA Polymerases......Page 537
4. MECHANISTIC MODELS OF TRANSLESION SYNTHESIS......Page 538
5.1. UV Photoproducts......Page 540
5.2. AP Sites......Page 541
5.3. 8-Oxoguanine......Page 542
5.5. BPDE-dG Adducts......Page 543
5.6. Cisplatin......Page 544
6. IMPORTANCE OF TRANSLESION SYNTHESIS IN EUKARYOTIC BIOLOGY......Page 545
REFERENCES......Page 546
1.1. Overall Structure of Saccharomyces cerevisiae polg......Page 554
1.2 Structure of the Sulfolobus DinB Family Members from......Page 558
2. DNA SYNTHESIS BY THE DINB FAMILY MEMBERS FROM THE SULFOLOBUS GENUS......Page 560
2.1. The Active Site of Dpo4......Page 563
2.2 Lesion Bypass......Page 564
3. DNA BINDING AND LESION BYPASS IN POLg......Page 566
4. RECRUITMENT OF Y-FAMILY DNA POLYMERASES......Page 568
5. LESION SPECIFICITY OF THE Y-FAMILY DNA POLYMERASES......Page 570
REFERENCES......Page 571
1. INTRODUCTION......Page 574
2. MECHANISMS OF DAMAGE BYPASS 2.1. Translesion Synthesis......Page 575
2.2. Damage Avoidance......Page 578
3. THE RAD6 PATHWAY......Page 579
3.1. Members of the RAD6 Pathway......Page 580
3.2. Genetic and Physical Interactions Within the RAD6 Pathway......Page 586
3.3. Proliferating Cell Nuclear Antigen Is a Target of the RAD6 Pathway......Page 588
4. PROLIFERATING CELL NUCLEAR ANTIGEN MODIFICATION BY THE UBIQUITIN-LIKE PROTEIN SUMO......Page 591
5. MECHANISTIC CONSIDERATIONS......Page 592
5.1. Upstream Signals......Page 593
5.2. Activation of TLS......Page 594
6. INTERACTIONS OF THE RAD6 PATHWAY WITH OTHER FACTORS......Page 595
6.2. Helicases and Strand-Annealing Factors......Page 596
7. SUMMARY AND OUTLOOK......Page 598
REFERENCES......Page 599
Part VI DNA Strand Breaks......Page 604
1. INTRODUCTION......Page 606
3.1. The Rad51 Protein......Page 607
3.3. The Rad54 Protein......Page 609
3.5. The Brca1 and Brca2 Proteins......Page 610
4. CELLULAR PROPERTIES OF HOMOLOGOUS RECOMBINATION PROTEINS 4.1. Local Accumulations of Proteins Involved in Homologous Recombination......Page 611
Table 1......Page 613
4.4. Colocalization of Proteins in Foci......Page 622
4.6. Nuclear Dynamics of Homologous Recombination Proteins in Living Cells......Page 624
ABBREVIATIONS......Page 626
REFERENCES......Page 627
2. ESSENTIAL ASPECTS OF VERTEBRATE NONHOMOLOGOUS DNA END JOINING (NHEJ)......Page 634
3. OVERVIEW OF V(D)J RECOMBINATION AND ITS UTILIZATION OF NHEJ IN THE REJOINING PROCESS......Page 638
4. OVERVIEW OF IMMUNOGLOBULIN CLASS SWITCH RECOMBINATION AND ITS UTILIZATION OF NHEJ IN THE REJOINING PROCESS......Page 640
5. POINTS OF BIOCHEMICAL DETAIL IN THE NHEJ PATHWAY......Page 644
7. ARE THERE MULTIPLE NHEJ PATHWAYS?......Page 647
REFERENCES......Page 649
1.1. Variable (Diversity) Joining [V(D)J] Recombination......Page 654
1.3. Homologous Recombination......Page 656
1.4. Nonhomologous End Joining......Page 657
1.5. Telomeres......Page 658
2. THE KU AUTOANTIGEN 2.1. A Brief History......Page 659
2.2. Structure......Page 660
2.3. Structural Implications for Ku’s Role in Transcription and DNA Replication......Page 665
2.4. Structural Implications for the Functions of the N- and C-Terminus of Ku70 and Ku86......Page 667
3. DNA-PKCS 3.1. A Brief History......Page 673
3.2. Structure......Page 675
3.3. Domains......Page 677
4.2. Telomere Length Maintenance......Page 680
4.3. G-Strand Overhang Maintenance......Page 684
4.4. Chromosomal Stability......Page 685
5. SUMMARY......Page 687
REFERENCES......Page 688
1. INTRODUCTION......Page 710
3. DNA LIGASE STRUCTURE......Page 711
4.1. LIG1 Gene and Products......Page 712
4.2. LIG3 Gene and Products......Page 714
4.3. LIG4 Gene and Products......Page 716
5.1. DNA Replication......Page 718
5.2. DNA Excision Repair......Page 719
5.4. Immunoglobulin Gene Rearrangement......Page 720
ACKNOWLEDGMENTS......Page 721
REFERENCES......Page 722
1. INTRODUCTION......Page 730
2. THE Mre11 COMPLEX 2.1. Identification of the Mre11 Complex......Page 731
2.2. The Mre11 Complex Is a Central Player in the Cellular Response to DSBs......Page 732
2.4. The Mre11 Complex Is a Multisubunit Machine......Page 733
3.1 DNA Processing Activity......Page 735
3.2. Damage Sensor and Checkpoint Functions......Page 736
3.3. Architectural Functions of the Mre11 Complex in Joining DSBs......Page 737
4. STRUCTURAL BIOCHEMISTRY OF THE Mre11 COMPLEX 4.1. Mre11 Nuclease......Page 739
4.2. The Mre11/Rad50 DNA End Detection/Processing Machine......Page 741
5. UNIFIED MODEL, CONCLUSIONS, AND OUTLOOK......Page 742
REFERENCES......Page 743
1. INTRODUCTION......Page 748
2.2 c-Phosphorylation Is Induced by Double-Strand Breaks Generated by Ionizing Radiation, Particle Emission and Radiomimetic Drugs......Page 749
2.3. Double-Strand Breaks Generated as Intermediates in DNA Metabolic Processes Induce c-Phosphorylation......Page 750
3. c-PHOSPHORYLATION OF H2A(X) SPANS MEGABASE-LONG DOMAINS IN CHROMATIN......Page 751
4. KINASES INVOLVED IN c-PHOSPHORYLATION OF H2A(X) HISTONE FAMILY......Page 752
5. RECRUITMENT OF REPAIR FACTORS TO c-PHOSPHORYLATED CHROMATIN......Page 753
6. MODELS AND SPECULATIONS ABOUT THE BIOLOGICAL ROLE OF c-H2AX FOCI......Page 754
ACKNOWLEDGMENTS......Page 756
REFERENCES......Page 757
2. INTRODUCTION......Page 762
3. NICK SENSOR FUNCTION OF PARP-1......Page 764
4. DUAL ROLE OF DNA-DAMAGE INDUCED PAR SYNTHESIS: BREAK SIGNALING AND RECRUITMENT OF XRCC1......Page 768
5. NO CROSS-TALK BETWEEN PAR SYNTHESIS AND c-H2AX FORMATION IN RESPONSE TO DNA-STRAND BREAK INJURY......Page 772
6. CONCLUSIONS AND FUTURE PROSPECTS......Page 774
REFERENCES......Page 775
Part VII Perception of DNA Damage for Initiating Regulatory Responses......Page 780
1.1. Exposure to Alkylating Agents and Relevance to Disease......Page 782
1.2. Types of Alkylating Agents and DNA Adducts Created......Page 783
1.3. Responses to Alkylation Damage: A Prospectus......Page 784
2.2. Ada Protein Structure and Function......Page 785
2.3. Genes Upregulated in the Adaptive Response......Page 787
2.4. Oxidative Demethylases......Page 789
2.5. The Adaptive Response in Eukaryotes......Page 790
3.3. MMR Recognition of Methylated Base Pairs......Page 791
3.4. Biological Effects on Mutagenicity and Toxicity in E. coli......Page 792
3.5. Mutagenicity and Toxicity in Human Cells......Page 793
4.1. Biochemical Basis for Toxicity......Page 796
4.2. Effect of 3MeA on Toxicity and Mutagenesis......Page 797
4.3. Initiation of Checkpoints and Apoptosis......Page 798
5. GENOME-WIDE ANALYSIS OF RESPONSES TO ALKYLATING AGENTS......Page 800
REFERENCES......Page 801
2. THE E. COLI SOS RESPONSE......Page 806
2.1. The SOS Regulon: Roles of the recA* and lexA* Genes......Page 807
3. STRUCTURE–FUNCTION OF THE LEXA PROTEIN FAMILY......Page 809
4. RECA PROTEIN–DNA INTERACTIONS AND LEXA SELF-CLEAVAGE......Page 811
5. ROLE OF DNA DAMAGE IN INDUCING THE E. COLI SOS RESPONSE......Page 814
5.2. SOS Induction by DNA Transposition......Page 815
6. UPREGULATION OF DNA REPAIR AND DNA DAMAGE TOLERANCE UNDER THE SOS RESPONSE......Page 816
6.1. Translesion DNA Synthesis: A Major Role of the SOS Response......Page 817
6.2. Coordinating DNA Replication, Recombination, and TLS Under the SOS Response......Page 818
7. AFTER THE DAMAGE IS REPAIRED: TURNING OFF THE SOS RESPONSE AND THE RETURN TO NORMALCY......Page 820
8. CONCLUDING REMARKS AND FUTURE PERSPECTIVES......Page 822
REFERENCES......Page 823
1. INTRODUCTION......Page 828
2. EARLY STUDIES CHARACTERIZING CHECKPOINT TRIGGERING DAMAGE AND SENSOR PROTEINS......Page 829
3. THE ATM PROTEIN IS A KINASE AND A PUTATIVE DAMAGE SENSOR......Page 830
4. THE ATR PROTEIN AND ITS TARGETING SUBUNIT......Page 832
5. PCNA- AND RFC-LIKE CLAMP AND CLAMP LOADER COMPLEXES FUNCTION AS DAMAGE SENSORS......Page 833
6. CROSSTALK BETWEEN SENSORS......Page 835
7. THE MRN COMPLEX PLAYS A ROLE IN CHECKPOINT ARRESTS......Page 836
9. THE GENERATION OF A TRANSDUCIBLE SIGNAL......Page 837
10. OTHER SENSOR CANDIDATES......Page 839
11. SENSING UV DAMAGE......Page 840
12. ADAPTATION AND CELL CYCLE RESTART......Page 841
REFERENCES......Page 843
1. INTRODUCTION......Page 852
2. HOW DO CELLS DEAL WITH A DAMAGED TEMPLATE DURING DNA REPLICATION?......Page 853
3. THE S-PHASE CHECKPOINT......Page 855
3.1. The Checkpoint Cascade......Page 856
3.2. Sensing DNA Damage During DNA Replication......Page 858
3.3. Checkpoint-Mediated Control of Replication......Page 860
REFERENCES......Page 862
Index......Page 866
Back cover......Page 896