DNA Repair And Mutagenesis

, by Friedberg, Errol C.; Walker, Graham C.; Siede, Wolfram; Schultz, Roger A.; Ellenberger, Tom

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ISBN: 9781555813192 | 1555813194
Cover: Hardcover
Copyright: 11/30/2005

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Univ. of Texas Southwestern, Dallas. Textbook features more than 10,000 references and 700 illustrations on DNA repair and mutagenesis. New edition presents recent developments over past decade. Topics include DNA damage, correcting altered bases, tolerance, regulatory responses to damage in eukaryotes, disease states, and more. Previous edition: c1995. For students.

Preface

xxv

Abbreviations

xxix

PART 1 Sources and Consequences of DNA Damage

(106)

Introduction: Biological Responses to DNA Damage

(6)

Historical Reflections

(1)

The Problem of Constant Genomic Insult

(1)

Biological Responses to DNA Damage

(2)

DNA Repair

(1)

DNA Damage Tolerance and Mutagenesis

(1)

Other Responses to DNA Damage

(1)

Disease States Associated with Defective Responses to DNA Damage

(3)

DNA Damage

(62)

Endogenous DNA Damage

(16)

Spontaneous Alterations in DNA Base Chemistry

(15)

Mismatches Created by DNA Replication Errors

(1)

Environmental DNA Damage

(23)

DNA Damage by Radiation

(10)

Chemical Agents That Damage DNA

(13)

DNA Damage and Chromatin Structure

(2)

UV Photoproduct Formation Is Influenced by Chromatin Structure and Binding of Other Proteins

(1)

Chromosomal Structure and Bound Proteins Can Protect against DNA Damage in Bacteria

(1)

Detection of DNA Damage by Proteins

(7)

Structural Information Is Encoded in DNA

(4)

Binding to Single-Stranded DNA

(1)

Locating Sites of DNA Damage

(2)

Summary and Conclusions

(14)

Introduction to Mutagenesis

(36)

Mutations and Mutants: Some Definitions

(4)

Point Mutations and Other Classes of Mutations

(1)

Base Substitution Mutations

(1)

Mutations Resulting from the Addition or Deletion of Small Numbers of Base Pairs

(1)

Systems Used To Detect and Analyze Mutations

(10)

Early Systems for the Analysis of Mutagenesis

(1)

The Ames Salmonella Test: a Widely Used Reversion System

(1)

E. coli Lacl: an Example of a Forward Mutational System

(1)

Other Examples of Forward Mutational Systems

(1)

Special Systems To Detect Frameshift or Deletion Mutations

(1)

Analysis of Mutagenesis in Mammalian Cells

(6)

Use of Site-Specific Adducts

(1)

Replication Fidelity and DNA Polymerase Structure

(12)

Templated Information in DNA

(1)

Energetics of Base Pairing

(1)

Geometric Selection of Nucleotides during DNA Synthesis

(3)

A Two-Metal-Ion Mechanism for DNA Synthesis

(2)

Open and Closed Conformations of DNA Polymerases

(1)

Importance of Base-Pairing Geometry versus Hydrogen Bonds

(1)

Selection against Ribonucleotides

(1)

Proofreading during DNA Synthesis

(2)

Lesion Bypass by Error-Prone DNA Polymerases

(3)

Conclusions about Replicative Fidelity

(1)

Mechanisms Contributing to Spontaneous Mutagenesis

(9)

Base Substitution Mutations Resulting from Misincorporation during DNA Synthesis

(1)

Mutations Resulting from Misalignments during DNA Synthesis

(8)

PART 2 Correcting Altered Bases in DNA: DNA Repair

107

(354)

Reversal of Base Damage Caused by UV Radiation

109

(30)

Direct Reversal Is an Efficient Strategy for Repairing Some Types of Base Damage Caused by UV Radiation

109

(1)

Enzymatic Photoreactivation of Base Damage Caused by UV Radiation

109

(3)

Not All Light-Dependent Recovery Effects Are Enzyme Catalyzed

110

(1)

Enzymatic Photoreactivation Was Discovered by Accident

110

(2)

Enzymes That Catalyze Photoreactivation of Cyclobutane Pyrimidine Dimers Are Members of an Extended Family of Blue-Light Receptor Proteins

112

(1)

Pyrimidine Dimer-DNA Photolyases

112

(16)

Distribution of Pyrimidine Dimer-DNA Photolyases in Nature

112

(1)

Measuring and Quantitating Pyrimidine Dimer-DNA Photolyase Activity

113

(1)

Properties and Mechanism of Action of Pyrimidine Dimer-DNA Photolyases

114

(5)

Structural Studies of Pyrimidine Dimer-DNA Photolyases

119

(2)

DNA Substrate Recognition and Electron Transfer by Photoproduct-DNA Photolyases

121

(2)

Pyrimidine Dimer-DNA Photolyases from Other Organisms

123

(4)

Therapeutic Use of Pyrimidine Dimer-DNA Photolyase for Protection against Sunlight

127

(1)

(6-4) Photoproduct-DNA Photolyases

128

(3)

(6-4) Photoproduct-DNA Photolyases Are Ubiquitous

128

(1)

Mechanism of Action of (6-4) Photoproduct-DNA Photolyases

129

(1)

The C-Terminal Region of (6-4) Photoproduct-DNA Photolyases Is Conserved

129

(2)

Reduced Dihydroflavin Adenine Dinucleotide Is the Active Form of (6-4) Photoproduct-DNA Photolyase

131

(1)

Photolyase/Blue-Light Receptor Family

131

(1)

Phylogenetic Relationships

132

(1)

Repair of Thymine Dimers by a Deoxyribozyme?

132

(1)

Photoreactivation of RNA

133

(1)

Reversal of Spore Photoproduct in DNA

133

(6)

Formation of Spore Photoproduct

133

(1)

Repair of Spore Photoproduct

134

(5)

Reversal of Alkylation Damage in DNA

139

(30)

Adaptive Response to Alkylation Damage in Bacteria

139

(2)

A Bit of History

139

(1)

The Adaptive Response Defined

140

(1)

Adaptation to Cell Killing and Adaptation to Mutagenesis Are Independent Processes

140

(1)

Repair of O6-Alkylguanine and O4-Alkylthymine in DNA

141

(16)

A New DNA Repair Mechanism

141

(1)

O6-Alkylguanine-DNA Alkyltransferases of E. coli

142

(4)

Role of Ada Protein in the Adaptive Response to Mutagenesis

146

(4)

O6-Alkylguanine-DNA Alkyltransferase II

150

(2)

DNA Alkyltransferases in Other Organisms

152

(5)

Repair of N1-Methyladenine and N3-Methylcytosine in DNA

157

(5)

alkB+ Gene of E. coli

157

(4)

Therapeutic Applications and Implications of the Repair of Alkylation Damage in DNA

161

(1)

Genetic Polymorphisms in the O6-MGMT Gene

162

(1)

Teleological Considerations Concerning the Reversal of Alkylation Base Damage in DNA

162

(1)

Repair of a Specific Type of Single-Stranded DNA Break by Direct Reversal

162

(1)

Summary and Conclusions

163

(6)

Base Excision Repair

169

(58)

DNA Glycosylases

169

(28)

Many DNA Glycosylases Are in the Helix-Hairpin-Helix Superfamily

171

(2)

Uracil-DNA Glycosylases Remove Uracil from DNA

173

(7)

Some DNA Glycosylases Remove Methylated Bases

180

(6)

Several Enzymes Function To Limit Oxidized and Fragmented Purine Residues

186

(5)

DNA Glycosylases That Remove Oxidized and Fragmented Pyrimidine Residues

191

(1)

Some Organisms Have Pyrimidine Dimer-DNA Glycosylases

192

(4)

Summary Comments on DNA Glycosylases

196

(1)

Apurinic/Apyrimidinic Endonucleases

197

(5)

Exonuclease III (XthA) Family of AP Endonucleases

198

(2)

Endonuclease IV (Nfo) Family of AP Endonucleases

200

(2)

Postincision Events during Base Excision Repair

202

(11)

Gap Filling and Deoxyribosephosphate Removal in E. coli

202

(1)

Gap Filling and Deoxyribosephosphate Removal in Mammalian Cells

203

(1)

Several Mechanisms Control the Fidelity of Base Excision Repair in Mammalian Cells

204

(1)

Structure and Mechanism of DNA Ligases

204

(6)

Polynucleotide Kinase Phosphatase in Base Excision Repair

210

(1)

Poly (ADP-Ribose) Polymerases in Base Excision Repair

210

(3)

Sequential Interactions between Proteins in Base Excision Repair

213

(1)

Base Excision Repair and Chromatin

214

(13)

Nucleotide Excision Repair: General Features and the Process in Prokaryotes

227

(40)

Introduction to Nucleotide Excision Repair

227

(1)

Historical Perspectives and Terminology

227

(1)

Revised Nomenclature for Nucleotide Excision Repair

228

(1)

Nucleotide Excision Repair in E. coli

228

(25)

UvrABC DNA Damage-Specific Endonuclease of E. coli

229

(1)

Damage-Specific Incision of DNA during Nucleotide Excision Repair in E. coli

229

(9)

Recognition of Base Damage during Nucleotide Excision Repair in E. coli

238

(6)

DNA Incision Is Bimodal during Nucleotide Excision Repair In Prokaryotes

244

(1)

A Second Endonuclease Can Catalyze 3' DNA Incision during Nucleotide Excision Repair in E. coli

245

(2)

Further Considerations about Nucleotide Excision Repair in Prokaryotes

247

(2)

Postincisional Events during Nucleotide Excision Repair: Excision of Damaged Nucleotides, Repair Synthesis, and DNA Ligation

249

(3)

Long-Patch Excision Repair of DNA

252

(1)

DNA Ligation

253

(1)

Miscellaneous Functions Possibly Associated with Nucleotide Excision Repair

253

(1)

Nucleotide Excision Repair in Other Prokaryotes

253

(2)

Micrococcus luteus

253

(1)

Deinococcus radiodurans

253

(1)

Other Organisms

254

(1)

Nucleotide Excision Repair Proteins Can Be Visualized in B. subtilis

254

(1)

Nucleotide Excision Repair Occurs in Some Members of the Archaea

255

(1)

Coupling of Transcription and Nucleotide Excision Repair in E. coli

255

(2)

mfd+ Gene and Transcription Repair Coupling Factor

255

(2)

Transcription Repair Coupling Factor Is Involved in Transcription Functions in the Absence of DNA Damage

257

(1)

Detection and Measurement of Nucleotide Excision Repair in Prokaryotes

257

(3)

Excision of Damaged Bases

257

(1)

Measurement of Repair Synthesis

258

(2)

Summary

260

(7)

Nucleotide Excision Repair in Eukaryotes: Cell Biology and Genetics

267

(50)

Cell Biology of Nucleotide Excision Repair in Eukaryotes

269

(5)

Experimental Demonstration of Nucleotide Excision Repair in Eukaryotic Cells

269

(5)

Kinetics of Nucleotide Excision Repair in Eukaryotic Cells

274

(1)

Genetics of Nucleotide Excision Repair in Eukaryotic Cells

274

(7)

Mammalian Cells

274

(2)

Genetics of Nucleotide Excision Repair in the Yeast S. cerevisiae

276

(2)

Genetics of Nucleotide Excision Repair in Other Eukaryotes

278

(3)

Genes and Proteins Involved in Nucleotide Excision Repair in Eukaryotes

281

(36)

Mammalian XPA and Its Yeast Ortholog RAD14

281

(1)

Replication Protein A

282

(2)

Budding Yeast RAD1 and RAD10, and the Mammalian Orthologs XPF and ERCC1

284

(7)

Yeast RAD2 and Its Mammalian Ortholog, XPG

291

(1)

Yeast RAD4, Mammalian XPC, and Their Association with Rad23 Homologs

292

(4)

Yeast and Mammalian Genes That Encode Subunits of TFIIH

296

(3)

MMS19 Gene and MMS19 Protein

299

(1)

Yeast RAD7 and RAD16 Genes and Rad7 and Rad16 Proteins

299

(2)

DNA Damage-Binding Protein and the Gene Defective in XP Group E

301

(2)

Understanding the Mechanism of Nucleotide Excision Repair

303

(14)

Mechanism of Nucleotide Excision Repair in Eukaryotes

317

(34)

Biochemical Strategies for Dissection of the Nucleotide Excision Repair Mechanism

318

(4)

Nucleotide Excision Repair in Cell Extracts

318

(2)

Permeabilized Cell Systems Can Identify Factors Involved in Nucleotide Excision Repair

320

(1)

Microinjection of DNA Repair Factors

321

(1)

Reconstitution of Nucleotide Excision Repair Defines the Minimal Components

322

(1)

Nucleotide Excision Repair in Mammalian Cells Can Be Reconstituted with Purified Components

322

(1)

Reconstitution of the Incision Reaction of Nucleotide Excision Repair in S. cerevisiae with Purified Components

323

(1)

TFIIH in Nucleotide Excision Repair: Creation of an Open Intermediate for Dual Incision

323

(4)

TFIIH Functions Independently in Nucleotide Excision Repair and in Transcription Initiation

323

(1)

TFIIH Harbors 10 Subunits and Two Enzymatic Activities

324

(1)

Core TFIIH Contains a Ring-Like Structure

325

(1)

TFIIH Performs Helix Opening in Transcription Initiation

325

(1)

TFIIH Performs Helix Opening during Nucleotide Excision Repair

326

(1)

Additional Functions of TFIIH

326

(1)

DNA Damage Recognition Mechanism in Nucleotide Excision Repair

327

(4)

Different Lesions Have Different Repair Efficiencies and Sites of Dual Incision

327

(1)

XPC-RAD23B as a Distortion Recognition Factor in Nucleotide Excision Repair

328

(1)

Bipartite Mechanism of DNA Damage Recognition during Nucleotide Excision Repair

328

(3)

Role of DDB Protein in Nucleotide Excision Repair

331

(1)

Mechanisms of Assembly and Action of the Nucleotide Excision Repair Machinery

331

(5)

Interactions between the Protein Components of Nucleotide Excision Repair

331

(1)

Nucleotide Excision Repair Subassemblies and Order of Action In Vitro

332

(2)

In Vivo Dynamics of Nucleotide Excision Repair

334

(2)

Repair Synthesis during Nucleotide Excision Repair

336

(3)

DNA Polymerases δ and ε and Their Participation in Nucleotide Excision Repair

336

(1)

Proliferating-Cell Nuclear Antigen in Nucleotide Excision Repair

337

(1)

Replication Factor C in Nucleotide Excision Repair

338

(1)

Oligonucleotide Excision and Ligation in Nucleotide Excision Repair

339

(1)

Oligonucleotide Excision during Nucleotide Excision Repair in Eukaryotes

339

(1)

DNA Ligation during Nucleotide Excision Repair in Eukaryotes

339

(1)

DNA Topoisomerases and Nucleotide Excision Repair

339

(1)

Modulation and Regulation of Nucleotide Excision Repair in Eukaryotes

340

(3)

The Proteasome and Regulation of Nucleotide Excision Repair

340

(2)

Protein Phosphorylation Influences Nucleotide Excision Repair

342

(1)

Evolution of the Eukaryotic Nucleotide Excision Repair System

343

(8)

Eukaryotic and Prokaryotic Nucleotide Excision Repair Mechanisms Use Similar Strategies

343

(1)

Most Eukaryotic Nucleotide Excision Repair Proteins Also Have Functions in Other Aspects of DNA Metabolism

343

(8)

Heterogeneity of Nucleotide Excision Repair in Eukaryotic Genomes

351

(28)

Influence of Chromatin and Higher-Order Structure on Nucleotide Excision Repair in Mammalian Cells

351

(8)

Chromatin Is Compactly Organized yet Subject to Dynamic Reorganization

351

(3)

Chromatin Remodeling and Nucleotide Excision Repair

354

(2)

Chromatin Reassembly Coupled to Nucleotide Excision Repair

356

(2)

Other Aspects of Intragenomic Heterogeneity of Nucleotide Excision Repair

358

(1)

Nucleotide Excision Repair in Transcribed versus Nontranscribed Regions

359

(12)

Introduction and Definition of Terms

359

(1)

Transcription-Coupled Nucleotide Excision Repair

360

(3)

Proteins That Participate in Transcription-Coupled Nucleotide Excision Repair

363

(2)

Cells Have Several Strategies To Deal with Stalled RNA Polymerase II

365

(3)

Biological Importance of Transcription-Coupled Nucleotide Excision Repair

368

(1)

Other Aspects of Transcription-Coupled Nucleotide Excision Repair

369

(2)

Summary

371

(8)

Alternative Excision Repair of DNA

379

(10)

Alternative Excision Repair Involving Endonuclease V

379

(4)

Endonuclease V of E. coli

379

(1)

Deoxyinosine 3' Endonuclease of E. coli

380

(1)

Endonuclease V and Deoxyinosine 3' Endonuclease of E. coli Are the Same Protein, Encoded by the E. coli nfi+ Gene

380

(1)

Endonuclease V of E. coli Is Conserved

380

(1)

Mammalian Homolog of Endonuclease V

381

(1)

Endonuclease V of E. coli Prevents Mutations Associated with Deamination of Bases

382

(1)

Nitrosating Agents Can Damage DNA

382

(1)

Endonuclease V of E. coli Prevents Cell Death Associated with the Presence of Hydroxylaminopurine in DNA

383

(1)

How Does Endonuclease V-Mediated Alternative Excision Repair Occur?

383

(1)

Alternative Excision Repair Mediated by Other Endonucleases

383

(4)

S. pombe DNA Endonuclease

383

(1)

S. pombe DNA Endonuclease in Other Organisms

384

(1)

What Is the Substrate Specificity of UVDE-Type Endonucleases?

385

(1)

Other Substrates Recognized by UVDE-Type Endonucleases

385

(1)

Uvel-Dependent Alternative Excision Repair of Mitochondrial DNA in S. pombe

385

(1)

How Does Uvel-Dependent Alternative Excision Repair Transpire?

386

(1)

Other Alternative Excision Repair Pathways?

386

(1)

Tyrosyl-DNA Phosphodiesterase: a Repair Reaction for Topoisomerase-DNA Complexes

387

(1)

Summary

387

(2)

Mismatch Repair

389

(60)

Early Biological Evidence for the Existence of Mismatch Repair

390

(1)

Genetic Phenomena Suggesting the Existence of Mismatch Repair

390

(1)

DNA Mismatch Repair in Prokaryotes

390

(12)

Mismatch Repair after Transformation of S. pneumoniae

391

(1)

In Vivo Analyses of Methyl-Directed Mismatch Repair in E. coli

392

(4)

Biochemical Pathway of E. coli Methyl-Directed Mismatch Repair

396

(6)

DNA Mismatch Repair in Eukaryotes

402

(7)

Early In Vivo Evidence Suggesting the Existence of Mismatch Repair in Yeasts and Fungi

402

(1)

MutS and MutL Homologs in Eukaryotic Cells

403

(3)

Defects in Mismatch Repair Genes Are Associated with Hereditary Nonpolyposis Colon Cancer

406

(1)

In Vitro Analyses of Mismatch Repair in Eukaryotic Cells

406

(3)

Relationship of Structure to Function of Mismatch Repair Proteins

409

(4)

MutS Structure

409

(2)

MutH Structure

411

(1)

MutL Structure

412

(1)

Unresolved Issues Concerning the Mechanism of Mismatch Repair

413

(3)

Molecular Basis of Strand Discrimination during Mismatch Repair

413

(1)

How Are Downstream Events Signaled in Mismatch Repair?

413

(3)

Effects of DNA Mismatch Repair on Genetic Recombination

416

(6)

Effect of Mismatch Repair on Recombination between Highly Homologous Sequences

416

(1)

Effects of Mismatch Repair on Recombination between Substantially Diverged Sequences

417

(5)

Effects of Mismatch Repair on Speciation, Adaptation, and Evolution

422

(2)

Possible Role for Mismatch Repair in Speciation

422

(1)

Cyclical Loss and Reacquisition of Mismatch Repair Play a Role in the Evolution of Bacterial Populations

422

(1)

Effects of Mismatch Repair on Adaptive Mutagenesis

423

(1)

Special Implications of Mismatch Repair Status for Pathogenic Bacteria

424

(1)

Mismatch Repair and Meiosis

424

(3)

Roles for Mismatch Repair Proteins in Gene Conversion and Antirecombination during Meiosis

424

(1)

Roles for Mismatch Repair Proteins in Promoting Crossovers during Meiosis

424

(3)

Mismatch Repair Proteins and DNA Damage Recognition

427

(2)

Mismatch Repair Proteins and Alkylation Damage

427

(2)

Oxidative DNA Damage and Mismatch Repair

429

(1)

Cisplatin DNA Damage and Mismatch Repair

429

(1)

Mismatch Repair and Other Forms of DNA Damage

429

(1)

Roles of Mismatch Repair Proteins in Somatic Hypermutation and Class Switch Recombination in the Immune Response

429

(1)

Somatic Hypermutation

430

(1)

Class Switch Recombination

430

(1)

Are the Effects of Mismatch Repair Proteins on Somatic Hypermutation and Class Switch Recombination Direct or Indirect?

430

(1)

Mismatch Repair and Cadmium Toxicity

430

(1)

Specialized Mismatch Repair Systems

431

(18)

Very-Short-Patch Mismatch Correction in E. coli Corrects G-T Mismatches Generated by Deamination of 5-Methylcytosine

431

(2)

Correction of G-T Mismatches Generated by Deamination of 5-Methylcytosine in Eukaryotes

433

(1)

MutY-Dependent Mismatch Repair

433

(16)

Repair of Mitochondrial DNA Damage

449

(12)

Mitochondrial DNA

449

(2)

The Mitochondrial Genome

449

(1)

Mitochondrial Mutagenesis

449

(2)

DNA Damage in the Mitochondrial Genome

451

(1)

Mitochondrial DNA Repair

451

(6)

Reversal of Base Damage in Mitochondrial DNA

452

(1)

Mitochondrial Base Excision Repair

452

(1)

Monitoring Loss of Damage from Mitochondrial DNA

453

(1)

Removal of Oxidative Damage from Mitochondrial DNA

453

(1)

Enzymes for Base Excision Repair in Mitochondrial Extracts

454

(1)

Short-Patch Base Excision Repair of Mitochondrial DNA

455

(1)

Age-Related Studies of Mitochondrial DNA Repair

455

(1)

Alternative Excision Repair Pathway in Mitochondria?

456

(1)

Recombinational Repair in Mitochondrial DNA?

457

(1)

Summary

457

(4)

PART 3 DNA Damage Tolerance and Mutagenesis

461

(290)

The SOS Responses of Prokaryotes to DNA Damage

463

(46)

The SOS Responses

463

(2)

Current Model for Transcriptional Control of the SOS Response

464

(1)

Physiological and Genetic Studies Indicate the Existence of the SOS System

465

(4)

Induced Responses

465

(1)

Genetic Studies of recA and lexA

466

(3)

Essential Elements of SOS Transcriptional Regulation

469

(9)

Proteolytic Cleavage of λ Repressor during SOS Induction

470

(1)

Induction of RecA Protein

471

(1)

LexA Protein Represses Both the recA+ and lexA+ Genes

471

(1)

LexA Protein Is Proteolytically Cleaved in a RecA-Dependent Fashion

472

(1)

Mechanism of LexA Repressor Cleavage

473

(3)

Similarities between LexA, λ Repressor, UmuD, and Signal Peptidase

476

(1)

Nature of the RecA Interactions Necessary for LexA, UmuD, and λ Repressor Cleavage

477

(1)

Identification of Genes in the SOS Network

478

(3)

Identifying SOS Genes by the Use of Fusions

478

(1)

Identifying SOS Genes by Searching for Potential LexA-Binding Sites

479

(1)

Identifying SOS Genes by Expression Microarray Analysis

479

(2)

Generation of the SOS-Inducing Signal In Vivo

481

(5)

Double-Strand Breaks Are Processed by the RecBCD Nuclease/Helicase To Give Single-Stranded DNA Needed for SOS Induction

483

(1)

Generation of Single-Stranded DNA by Bacteriophage, Plasmids, or Transposons Leads to SOS Induction

483

(1)

An SOS-Inducing Signal Is Generated when Cells Attempt To Replicate Damaged DNA

484

(1)

Regions of Single-Stranded DNA in Undamaged Cells

485

(1)

SOS Induction Caused by Mutations That Affect the Normal Processing of DNA

485

(1)

The Special Case of Phage φ80 Induction

486

(1)

Modeling the SOS Signal

486

(1)

Additional Subtleties in the Transcriptional Regulation of the SOS Responses

486

(5)

Strength and Location of SOS Boxes

486

(2)

DinI, RecX, and PsiB Proteins and isfA Affect SOS Regulation by Modulating RecA-Mediated Cleavage Reactions

488

(1)

Other Regulatory Systems Can Affect the Expression of SOS-Regulated Genes

489

(1)

Physiological Considerations of the SOS Regulatory Circuit

489

(2)

Levels of Control of the SOS Response besides Transcriptional Regulation

491

(1)

A Physiological Look at the SOS Responses

491

(5)

SOS-Induced Responses That Promote Survival while Maintaining the Genetic Integrity of the Genome

491

(1)

SOS-Induced Responses That Promote Survival while Destabilizing the Genetic Integrity of the Genome

492

(1)

SOS-Induced Responses That Destabilize the Genetic Integrity of the Genome

493

(2)

SOS-Induced Cell Cycle Checkpoints

495

(1)

Miscellaneous Physiological Effects of SOS Induction

495

(1)

SOS Responses in Pathogenesis and Toxicology

496

(1)

Relationships of the SOS Responses to Pathogenesis

496

(1)

Use of Fusions to SOS Genes To Detect Genotoxic Agents

497

(1)

SOS Responses in Other Bacteria

497

(12)

Mutagenesis and Translesion Synthesis in Prokaryotes

509

(60)

SOS-Dependent Mutagenesis: Requirements for Particular Gene Products

510

(13)

SOS Mutagenesis by UV Radiation and Most Chemicals Is Not a Passive Process

510

(1)

UmuD and UmuC Proteins Are Important for UV Radiation and Chemical Mutagenesis

511

(3)

Multiple Levels of Post-Translational Regulation of UmuD Protein: New Dimensions to SOS Regulation

514

(9)

Inferences about the Mechanism of SOS Mutagenesis Based on Mutational Spectra and Site-Directed Adduct Studies

523

(12)

The Original lacl System: a Purely Genetic Means of Determining Mutational Spectra

523

(1)

Mutational Spectra Obtained by Direct DNA Sequencing

524

(1)

Factors Influencing the Mutational Spectrum for a Given Mutagen

524

(1)

Influence of Transcription-Coupled Excision Repair on Mutational Spectra

525

(1)

Identification of Premutagenic Lesions

525

(7)

More Complex Lesions as Premutagenic Lesions

532

(2)

SOS Mutator Effect

534

(1)

The Road to Discovering the Molecular Mechanism of SOS Mutagenesis

535

(4)

A Further Requirement for RecA Protein in SOS Mutagenesis besides Facilitating LexA and UmuD Cleavage

535

(1)

DNA Polymerases I and II Are Not Required for SOS Mutagenesis

536

(1)

Evidence Relating DNA Polymerase III to SOS Mutagenesis

536

(1)

Influence of the ``Two-Step'' Model for SOS Mutagenesis

537

(1)

Initial Efforts To Establish an In Vitro System for SOS Mutagenesis

537

(1)

UmuC-Related Proteins Are Found in All Three Kingdoms of Life

538

(1)

dinB, umuDC, and mucAB Encode Members of the Y Family of Translesion DNA Polymerases

539

(4)

Rev1 Catalyzes the Formation of Phosphodiester Bonds: Rad30 and Xeroderma Pigmentosum Variant Protein Are DNA Polymerases

539

(1)

DinB Is a DNA Polymerase

539

(1)

umuDC Encodes a Translesion DNA Polymerase, DNA Pol V, That Requires Accessory Proteins

540

(2)

mucAB Encodes a Translesion DNA Polymerase, DNA Pol R1, That Requires Accessory Proteins

542

(1)

The Structure of Family Y DNA Polymerases Accounts for Their Special Ability To Carry Out Translesion Synthesis

543

(1)

Multiple SOS-Induced DNA Polymerases Can Contribute to SOS-Induced Mutagenesis

543

(1)

Protein-Protein Interactions That Control the Activities of the umuDC and dinB Gene Products

543

(8)

RecA and SSB Interactions with DNA Pol V

545

(1)

Interactions of the β Sliding Clamp with DNA Polymerases V and IV

546

(2)

Interactions of UmuD and UmuD' with Components of DNA Polymerase III

548

(1)

How Is Polymerase Switching Controlled?

549

(2)

What Is the Biological Significance of SOS Mutagenesis and Translesion Synthesis by Specialized DNA Polymerases?

551

(3)

Translesion DNA Polymerases Can Contribute to Fitness and Survival in Two Ways

551

(1)

Action of Translesion DNA Polymerases in Stationary Phase, Aging, and Stressed Bacteria

551

(3)

SOS-Independent Mutagenesis

554

(15)

Lesions That Do Not Require Induction of SOS Functions To Be Mutagenic

554

(1)

The UVM (UV Modulation of UV Mutagenesis) Response

555

(1)

Mutagenesis Resulting from the Misincorporation of Damaged Nucleotides

555

(14)

Recombinational Repair, Replication Fork Repair, and DNA Damage Tolerance

569

(44)

DNA Damage Can Interfere with the Progress of Replication Forks and Lead to the Generation of Various Structures

570

(4)

Formal Considerations

570

(1)

The In Vivo Situation Is More Complicated

571

(2)

Transient Partial Inhibition of DNA Replication after DNA Damage

573

(1)

Various DNA Structures Resulting Directly or Indirectly from DNA Damage Can Be Processed by Homologous Recombination Proteins

574

(10)

RecA Protein: a Protein with Mechanistic Roles in Homologous Recombination and DNA Repair

574

(5)

Other Key Proteins with Roles in Homologous Recombination

579

(5)

Recombinational Repair of Double-Strand Breaks in E. coli

584

(2)

Model for Damage Tolerance Involving the Recombinational Repair of Daughter Strand Gaps

586

(7)

Evidence Supporting the Model for Recombinational Repair of Daughter Strand Gaps

586

(4)

Perspectives on Daughter Strand Gap Repair

590

(2)

An Error-Free Process(es) Involving Recombination Functions Predominates over Mutagenic Translesion Replication in a Model In Vivo System

592

(1)

Homologous Recombination Functions Play Critical Roles in the Stabilization and Recovery of Arrested or Collapsed Replication Forks

593

(5)

Recognition of Fundamental Relationships between Replication and Recombination

593

(5)

Possible Mechanisms for Regressing Replication Forks

598

(5)

Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks Arrested by a Lesion Affecting Only One Strand of the DNA Template

599

(3)

Models of Nonmutagenic Mechanisms for Restarting Regressed DNA Replication Forks Arrested by a Lesion or Blocks Affecting Both Strands of the DNA Template

602

(1)

Recovery of DNA Replication after DNA Damage: ``Inducible Replisome Reactivation/Replication Restart''

603

(10)

Polymerases Participating in Inducible Replisome Reactivation/Replication Restart Revisited

603

(10)

DNA Damage Tolerance and Mutagenesis in Eukaryotic Cells

613

(50)

Phenomenology of UV Radiation-Induced Mutagenesis in the Yeast Saccharomyces cerevisiae

613

(4)

Insights from Mutational Spectra: the SUP4-o System

613

(2)

Studies with Photoproducts at Defined Sites

615

(1)

Untargeted Mutagenesis in S. cerevisiae Cells Exposed to UV Radiation

616

(1)

Timing and Regulation of UV Radiation-Induced Mutagenesis

616

(1)

Phenomenology of UV Radiation-Induced Mutagenesis in Mammalian Cells

617

(12)

DNA Replication in UV-Irradiated Cells

617

(4)

Inducibility of Mutagenic Processes in Mammalian Cells?

621

(1)

Mutational Specificity of UV Radiation-Induced Lesions

622

(7)

Summary and Conclusions

629

(1)

Molecular Mechanisms of Eukaryotic DNA Damage Tolerance and Mutagenesis

629

(20)

Genetic Framework in S. cerevisiae

629

(1)

DNA Polymerase ζ

629

(2)

Rev1 Protein

631

(1)

DNA Polymerase η

632

(4)

Other Vertebrate Lesion Bypass Polymerases

636

(2)

Handling of DNA Lesions by Bypass Polymerases: Synopsis and Comparison with In Vivo Data

638

(1)

Somatic Hypermutation

639

(3)

The RAD6 Epistasis Group Dissected: Defining Error-Prone and Error-Free Tolerance Mechanisms

642

(5)

Role of PCNA in Orchestrating the Choice of Damage Tolerance Pathways

647

(2)

Summary and Conclusions

649

(14)

Managing DNA Strand Breaks in Eukaryotic Cells: Repair Pathway Overview and Homologous Recombination

663

(48)

Overview of Various Pathways for Double-Strand Break Repair in Eukaryotes

663

(2)

Saccharomyces cerevisiae as a Model System for Detecting Double-Strand Breaks and Their Repair

665

(3)

Experimental Systems To Study Responses to Localized DNA Double-Strand Breaks

668

(3)

The HO Endonuclease System

668

(1)

Generation of Double-Strand Breaks in Conditional Dicentric Chromosomes

668

(1)

I-SceI-Induced Targeted Double-Strand Breaks

669

(2)

Homologous Recombination

671

(16)

End Processing as the Initiating Step

671

(1)

Pairing and Exchanging of Homologous DNA: Rad51, Its Orthologs, Paralogs, and Interacting Partners

671

(10)

Role of Cohesin Proteins

681

(1)

The BRCA/Fanconi Pathway

682

(3)

Holliday Structure Resolution

685

(2)

Synthesis-Dependent Strand Annealing and Break-Induced Replication

687

(1)

Single-Strand Annealing

688

(1)

Transcription and Recombination

689

(1)

UV Radiation-Stimulated Recombination

690

(1)

Repair of DNA Interstrand Cross-Links

690

(6)

Interstrand Cross-Link Repair in E. coli

691

(1)

Interstrand Cross-Link Repair in S. cerevisiae

692

(3)

Interstrand Cross-Link Repair in Higher Eukaryotes

695

(1)

Summary

696

(15)

Managing DNA Strand Breaks in Eukaryotic Cells: Nonhomologous End Joining and Other Pathways

711

(40)

Nonhomologous End Joining

711

(13)

Introduction

711

(1)

V(D)J Recombination

712

(2)

Class Switch Recombination

714

(1)

Roles of the Ku Proteins

715

(3)

DNA-Dependent Protein Kinase

718

(3)

Artemis: a Human SCID Syndrome Reveals a Player in Nonhomologous End Joining

721

(1)

Ligation Step of Nonhomologous End Joining

722

(2)

Synopsis: Model for Vertebrate Nonhomologous End Joining

724

(1)

The Mrell-Rad50-NBSI/Xrs2 Complex

724

(11)

Yeast Rad50, Mre11, and Xrs2 Function in Double-Strand Break Repair and Meiosis but Are Not Essential for Homologous Recombination

725

(1)

Two MRN Complex Components Are Associated with Human Genomic Instability Syndromes

726

(1)

Null Mutations of MRN Components Are Lethal in Mammalian Cells, and Hypomorphic Mutations Result in Severe Developmental Consequences

726

(1)

Focus Formation of the MRN Complex at Sites of Double-Strand Breaks

727

(1)

In Vitro DNA-Processing Activities of the MRN Complex

727

(1)

The MRN Complex in Nonhomologous DNA End Joining: a Major Role in S. cerevisiae but Possibly Not in Vertebrates

728

(2)

Role of the MRN Complex in Homologous Recombination

730

(1)

Significance of Nuclease Activity

731

(1)

Special Roles of the MRN Complex in Replication and Telomere Maintenance

731

(2)

``Molecular Velcro'' and Beyond: Models for MRN Action Based on Structural Analysis

733

(1)

Conclusions

734

(1)

Histone Modifications and Double-Strand Breaks

735

(1)

Histone Phosphorylation

735

(1)

Histone Acetylation

736

(1)

Regulation of Pathway Choice

736

(1)

Repair of Single-Strand Breaks

737

(14)

Sources and Significance of Single-Strand Breaks

737

(1)

Poly(ADP-Ribose) Polymerase as a Nick Sensor

738

(1)

XRCC1 Is a Scaffold Protein Orchestrating Interactions among Multiple Single-Strand Break Repair Proteins

738

(13)

PART 4 Regulatory Responses to DNA Damage in Eukaryotes

751

(112)

Cell Cycle Checkpoints: General Introduction and Mechanisms of DNA Damage Sensing

753

(26)

Cell Cycle Basics and the Emergence of the Checkpoint Concept

753

(5)

Studying Checkpoints

757

(1)

DNA Damage Sensing

758

(21)

Defining Checkpoint-Triggering Damage and Sensor Proteins

758

(2)

The ATM Protein as a Damage Sensor

760

(2)

ATR Protein and Its Targeting Subunit

762

(2)

PCNA- and RFC-Like Clamp and Clamp Loader Complexes

764

(1)

Cross Talk between Sensors

765

(1)

The MRN Complex Plays an Additional Role in Checkpoint Arrests

766

(1)

Synopsis: Independent but Communicating Sensors Are Brought Together by Common Requirements

767

(1)

Other Sensor Candidates

768

(1)

Sensing UV Radiation Damage

768

(1)

Damage Sensing in S Phase

769

(10)

Cell Cycle Checkpoints: Signal Transmission and Effector Targets

779

(38)

Generation and Transmission of a Checkpoint-Activating Signal

779

(6)

The Rad53Sc/Cds1Sp/CHK2Hs Kinase

779

(2)

Mediators Are Important for Activation of Rad53Sc/Cds1Sc/CHK2Hs through DNA Structure Sensors

781

(1)

Possible Mammalian Rad9Sc Homologs

782

(1)

S-Phase-Specific Activation of Rad53Sc/Cds1Sp/CHK2Hs

783

(1)

Chk1 Kinase: Different Roles in Different Organisms

783

(1)

Activation of Chk1 Kinase in S. pombe, X. laevis, and Humans

784

(1)

Summary: Pathways of Generating a Transmittable Damage Signal

784

(1)

Downstream Targets and Mechanisms That Regulate Cell Cycle Progression

785

(17)

p53 as a Target of DNA Checkpoint Pathways

785

(6)

DNA Damage-Induced G1/S Arrest

791

(3)

Modulation of S Phase in the Presence of DNA Damage

794

(4)

DNA Damage-Induced G2/M Arrest

798

(3)

DNA Damage and the Regulation of M Phase

801

(1)

Synopsis

802

(1)

Effector Targets That Modulate DNA Repair

802

(1)

Repair Targets in Yeasts

802

(1)

Repair Targets in Mammalian Cells

803

(1)

Other Regulatory Responses to DNA Damage

803

(1)

Summary

804

(13)

Transcriptional Responses to DNA Damage

817

(28)

Introduction

817

(1)

Phenotypic Characterization of Pathway Inducibility

817

(1)

Analysis of Individual Genes

817

(1)

Differential Screening

818

(1)

Screens of Genome Arrays

818

(1)

Saccharomyces cerevisiae Genes Regulated in Response to DNA-Damaging Agents

818

(10)

Regulation of Ribonucleotide Reductase

818

(2)

Inducibility of Genes Involved in DNA Repair and Damage Tolerance: a Look at Various Pathways

820

(3)

Genome-Wide Approaches

823

(4)

Synopsis: No Satisfying Answer to the Question of Significance

827

(1)

Vertebrate Genes Regulated in Response to DNA-Damaging Agents

828

(9)

Overview

828

(1)

p53 as a Transcription Factor

828

(2)

E2F Transcription Factor Family

830

(1)

Mammalian UV Radiation Response

831

(4)

Transcriptional Response to Ionizing Radiation

835

(2)

Summary and Conclusions

837

(8)

DNA Damage and the Regulation of Cell Fate

845

(18)

Adaptation and Cell Cycle Restart

846

(2)

Damage Signaling and Adaptation in Saccharomyces cerevisiae

846

(1)

Adaptation and Cell Cycle Restart by Silencing of Downstream Effectors

847

(1)

Recovery in Multicellular Eukaryotes

847

(1)

Regulation of Apoptosis

848

(6)

Introduction to Apoptotic Pathways

848

(2)

Activation of the Apoptosis Pathway by DNA Damage: the Roles of p53 Revisited

850

(2)

Role of DNA Damage Sensors and Transducers in Apoptosis

852

(1)

Additional Elements of DNA Damage-Induced Apoptosis

853

(1)

Senescence, Cancer, and the DNA Damage Connection

854

(2)

Checkpoints and Cancer Therapy

856

(7)

PART 5 Disease States Associated with Defective Biological Responses to DNA Damage

863

(218)

Xeroderma Pigmentosum: a Disease Associated with Defective Nucleotide Excision Repair or Defective Translesion DNA Synthesis

865

(30)

A Huge Literature on Xeroderma Pigmentosum

865

(1)

Primary Clinical Features

866

(1)

Other Clinical Features

867

(1)

Incidence and Demographics

867

(1)

Skin Cancer Associated with Xeroderma Pigmentosum

868

(1)

Phenotypes of Xeroderma Pigmentosum Cells

868

(6)

Chromosomal Abnormalities

868

(1)

Sensitivity to Killing by DNA-Damaging Agents

869

(1)

Hypermutability

869

(1)

Source of Mutations

869

(1)

Defective Nucleotide Excision Repair

870

(2)

Repair of Oxidative Damage and Its Relationship to Neurological Disorders in Xeroderma Pigmentosum

872

(1)

Defective Repair of Purine Cyclodeoxynucleosides

873

(1)

Genetic Complexity of Xeroderma Pigmentosum

874

(1)

The Xeroderma Pigmentosum Heterozygous State

875

(1)

Molecular Pathology

875

(7)

Xeroderma Pigmentosum from Genetic Complementation Group A

875

(1)

Xeroderma Pigmentosum from Genetic Complementation Group B

876

(1)

Xeroderma Pigmentosum from Genetic Complementation Group C

877

(1)

Xeroderma Pigmentosum from Genetic Complementation Group D

878

(2)

Xeroderma Pigmentosum from Genetic Complementation Group E

880

(1)

Mutations Have Only Been Found in the DDB2 Gene in XP-E Group Cells

880

(1)

Xeroderma Pigmentosum from Genetic Complementation Group F

880

(1)

Xeroderma Pigmentosum from Genetic Complementation Group G

881

(1)

Summary

881

(1)

Unexplained Features of Xeroderma Pigmentosum

881

(1)

Cancer in Other Organs in Xeroderma Pigmentosum Individuals

881

(1)

Cancer Risk Assessment

882

(1)

Pathogenesis of Neurological Complications

882

(1)

Therapy

882

(1)

Mouse Models of Defective Nucleotide Excision Repair

882

(5)

Mice Defective in the Xpa Gene

883

(1)

Mice Defective in the Xpc Gene

884

(2)

Mice Defective in the Xpd Gene

886

(1)

Mice Defective in the Xpe Gene

886

(1)

Mice Defective in the Xpf Gene

887

(1)

Mice Defective in the Xpg Gene

887

(1)

Mice Defective in the Erccl Gene

887

(1)

Mice Defective in the Rad23A and Rad23B Genes

887

(1)

Summary

887

(8)

Other Diseases Associated with Defects in Nucleotide Excision Repair of DNA

895

(24)

Cockayne Syndrome

895

(10)

Introduction

895

(1)

Clinical Phenotypes

895

(1)

Cellular Phenotypes

896

(2)

Genetics

898

(7)

Other Clinical Entities Associated with Mutations in Cockayne Syndrome or XP Genes

905

(8)

Cerebro-Oculo-Facio-Skeletal Syndrome

905

(1)

UV Sensitive Syndrome

905

(1)

Combined XP/CS Complex

906

(1)

Allelic Heterogeneity in Xeroderma Pigmentosum

906

(1)

Trichothiodystrophy

907

(2)

The ``Transcription Syndrome'' Hypothesis of XP/CS and Trichothiodystrophy

909

(1)

Direct Observations of Defective Transcription

910

(1)

Molecular Defects in XP/CS and Trichothiodystrophy Cells

910

(2)

Allele-Specific and Gene Dosage Effects in This Group of Diseases

912

(1)

Skin Cancer in the Transcription Syndromes

913

(1)

Summary

913

(6)

Diseases Associated with Defective Responses to DNA Strand Breaks

919

(28)

Ataxia Telangiectasia (Louis-Bar Syndrome)

919

(9)

Clinical Features

919

(1)

Cellular Phenotypes

920

(4)

Identification of the Ataxia Telangiectasia-Mutated (ATM) Gene

924

(2)

Atm Mutant Mice

926

(2)

Nijmegen Breakage Syndrome

928

(2)

Clinical Features

928

(1)

Cellular Characteristics

928

(1)

Identification of the Gene Mutated in Nijmegen Breakage Syndrome (NBS1)

929

(1)

Nibrin and Nijmegen Breakage Syndrome Cellular Phenotypes

929

(1)

Nbs1 Mutant Mice

929

(1)

Genetic Heterogeneity

929

(1)

Heterozygosity and Cancer Predisposition

930

(1)

Ataxia Telangiectasia-Like Disorder

930

(1)

DNA Ligase IV Mutations and Human Disease

930

(1)

Seckel Syndrome

930

(2)

Severe Combined Immunodeficiency

932

(3)

Clinical Features

933

(1)

Molecular Causes

934

(1)

Recombinase-Activating Gene Deficiencies (RAG1- or RAG2-Deficient Severe Combined Immunodeficiency)

935

(1)

Animal Models

935

(1)

Spinocerebellar Ataxia with Axonal Neuropathy

935

(12)

Diseases Associated with Disordered DNA Helicase Function

947

(32)

Biochemistry of RecQ Helicases

947

(6)

Crystal Structures of DNA Helicases

949

(1)

Fluorescence Resonance Energy Transfer

950

(2)

DNA Helicases That Participate in DNA Replication

952

(1)

RecQ Helicases and Human Disease

953

(1)

RecQ Helicases in Model Organisms

953

(1)

RecQ Protein in E. coli

953

(1)

Yeast Homologs of RecQ

954

(1)

Bloom Syndrome

954

(11)

Clinical Features of Bloom Syndrome Include a Marked Cancer Predisposition

955

(1)

Autosomal Recessive Genetics of Bloom Syndrome

955

(1)

Chromosome Instability as a Hallmark of Bloom Syndrome Cells

955

(1)

Bloom Syndrome Cells Exhibit Defects Associated with the S Phase of the Cell Cycle

956

(1)

Bloom Syndrome Cells Manifest a Diversity of Subtle Defects in Enzymes Involved in DNA Repair

957

(1)

Somatic Recombination Events in Bloom Syndrome Cells Facilitate Mapping and Cloning of the BLM Gene

958

(1)

Interallelic Recombination and Its Potential Relevance to Bloom Syndrome

958

(1)

The BLM Gene Is a Member of the RecQ Family

958

(1)

Bloom Syndrome Heterozygotes May Be Predisposed to Cancer

959

(1)

The BLM Gene Product Is a RecQ-Like Helicase

960

(1)

BLM Gene Expression

960

(1)

BLM Protein Localization

961

(1)

Modulation of Sister Chromatid Exchange

961

(1)

Association of BLM with Other DNA Repair Functions

962

(1)

Models for the Study of BLM Function

963

(1)

The Molecular Function of BLM Protein

964

(1)

Werner Syndrome

965

(3)

Clinical Features

965

(1)

Genetics

966

(1)

Cellular Phenotype of Werner Syndrome Cells

966

(1)

Identification of the WRN Gene

966

(1)

WRN Protein Contains DNA Helicase and Exonuclease Activities

967

(1)

WRN Protein Interactions

967

(1)

WRN Expression

968

(1)

WRN Protein Function

968

(1)

Mutations in RECQL4 Are Associated with Rothmund-Thomson Syndrome and RAPADILINO Syndrome

968

(3)

Clinical Features of Rothmund-Thomson Syndrome

968

(1)

Cellular Characteristics of Rothmund-Thomson Syndrome

968

(1)

Rothmund-Thomson Syndrome Patients Have Mutations in RECQL4

969

(1)

RAPADILINO Syndrome

969

(2)

Summary of Human Diseases Associated with Defects in the RecQ Family of DNA Helicase

971

(8)

Additional Diseases Associated with Defective Responses to DNA Damage

979

(22)

Hereditary Nonpolyposis Colon Cancer

980

(6)

Clinical Presentation

980

(1)

Hereditary Nonpolyposis Colon Cancer and Microsatellite Instability

980

(1)

Hereditary Nonpolyposis Colon Cancer and Mismatch Repair

981

(3)

How Do Heterozygous Mutations Cause Cancer?

984

(1)

Mouse Models with Defects in Mismatch Repair Genes

985

(1)

Tumors in Homozygous Mutant Mice

985

(1)

Fanconi Anemia

986

(15)

Clinical Phenotypes

987

(1)

Genetics

988

(1)

Cellular Features

988

(1)

DNA Repair in Fanconi Anemia Cells

989

(1)

Genetic Complexity

989

(4)

Mouse Models

993

(1)

Final Comments

994

(7)

Hereditary Diseases That Implicate Defective Responses to DNA Damage

1001

(48)

Hereditary Cancer Predisposition Syndromes

1001

(20)

Retinoblastoma

1004

(2)

Li-Fraumeni Syndrome

1006

(1)

Breast Cancer Predisposition Syndromes

1007

(1)

Predisposition to Gastrointestinal Tumors

1008

(8)

Skin Cancer Syndromes

1016

(2)

Additional Cancer Predisposition Syndromes

1018

(3)

Disorders with Alterations in Chromatin Structure

1021

(7)

Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome

1021

(2)

Roberts Syndrome

1023

(2)

Alpha-Thalassemia/Mental Retardation Syndrome, X-Linked

1025

(1)

Rett Syndrome

1025

(1)

Rubinstein-Taybi Syndrome

1026

(1)

Coffin-Lowry Syndrome

1026

(1)

Saethre-Chotzen Syndrome

1026

(1)

Dyskeratosis Congenita

1027

(1)

DNA Repair and Its Association with Aging

1028

(21)

Aging and the Age-Related Decline in DNA Repair

1028

(2)

Reversal of Aging and DNA Repair

1030

(1)

Array Analysis of Aging in Mammals

1030

(1)

Engineered Mouse Models for Aging

1030

(1)

Telomeres and Aging

1031

(1)

Hutchinson-Gilford Progeria Syndrome (Progeria)

1032

(1)

Down Syndrome (Trisomy 21)

1033

(16)

DNA Polymorphisms in Gatekeeper and Guardian Genes

1049

(32)

Human Genetic Variation

1050

(2)

DNA Structure/Repair-Related Methodologies for Single-Nucleotide Polymorphism Detection

1052

(4)

Oligonucleotide Arrays

1052

(2)

Mismatch Repair Detection

1054

(1)

TDG/MutY Glycosylase Mismatch Detection

1054

(1)

MassEXTEND

1054

(1)

Stabilized Double D-Loops

1054

(2)

Assessing the Role of DNA Repair Gene Polymorphisms in Disease

1056

(6)

Statistics and Population-Based Studies

1056

(1)

Variability in DNA Repair Capacity

1057

(2)

Heterozygosity and DNA Repair Gene Mutations

1059

(1)

Heterozygosity for Genes Associated with Dominantly Inherited Disorders

1059

(2)

Heterozygosity for Genes Associated with Recessive Disorders

1061

(1)

Summarizing the Role of Heterozygosity

1061

(1)

DNA Repair Gene Polymorphisms

1062

(19)

DNA Repair Gene Single-Nucleotide Polymorphism Discovery

1062

(1)

Polymorphisms That Impact the Levels of Chemical-Induced DNA Damage

1062

(1)

Cytochrome P-450 Monooxygenase Gene

1062

(1)

Glutathione S-Transferase M1 Gene

1063

(1)

N-Acetyltransferase 2 Gene

1063

(1)

DNA Repair Gene Polymorphisms and Putative Cancer Risk

1064

(3)

Pharmacogenomics and DNA Repair Gene Polymorphisms

1067

(1)

Polymorphic Alleles and Functional Defects

1067

(3)

Summary

1070

(11)

Appendix

1081

(10)

Table 1 Nomenclature of DNA repair genes

1081

(6)

Table 2 Human hereditary diseases and defective cellular responses to DNA damage

1087

(4)

Index

1091

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DNA Repair And Mutagenesis

Summary

Table of Contents

Supplemental Materials