DNA Repair And Mutagenesis

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

• ISBN13: 9781555813192
• ISBN10: 1555813194
• Edition: 2nd
• Format: Hardcover
• Copyright: 2005-11-30
• Publisher: Amer Society for Microbiology

Summary

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.

Table of Contents

Preface	xxv
Abbreviations	xxix
PART 1 Sources and Consequences of DNA Damage	1	(106)
Introduction: Biological Responses to DNA Damage	3	(6)
Historical Reflections	3	(1)
The Problem of Constant Genomic Insult	4	(1)
Biological Responses to DNA Damage	4	(2)
DNA Repair	4	(1)
DNA Damage Tolerance and Mutagenesis	5	(1)
Other Responses to DNA Damage	6	(1)
Disease States Associated with Defective Responses to DNA Damage	6	(3)
DNA Damage	9	(62)
Endogenous DNA Damage	9	(16)
Spontaneous Alterations in DNA Base Chemistry	9	(15)
Mismatches Created by DNA Replication Errors	24	(1)
Environmental DNA Damage	25	(23)
DNA Damage by Radiation	25	(10)
Chemical Agents That Damage DNA	35	(13)
DNA Damage and Chromatin Structure	48	(2)
UV Photoproduct Formation Is Influenced by Chromatin Structure and Binding of Other Proteins	48	(1)
Chromosomal Structure and Bound Proteins Can Protect against DNA Damage in Bacteria	49	(1)
Detection of DNA Damage by Proteins	50	(7)
Structural Information Is Encoded in DNA	50	(4)
Binding to Single-Stranded DNA	54	(1)
Locating Sites of DNA Damage	55	(2)
Summary and Conclusions	57	(14)
Introduction to Mutagenesis	71	(36)
Mutations and Mutants: Some Definitions	71	(4)
Point Mutations and Other Classes of Mutations	73	(1)
Base Substitution Mutations	73	(1)
Mutations Resulting from the Addition or Deletion of Small Numbers of Base Pairs	74	(1)
Systems Used To Detect and Analyze Mutations	75	(10)
Early Systems for the Analysis of Mutagenesis	75	(1)
The Ames Salmonella Test: a Widely Used Reversion System	76	(1)
E. coli Lacl: an Example of a Forward Mutational System	77	(1)
Other Examples of Forward Mutational Systems	78	(1)
Special Systems To Detect Frameshift or Deletion Mutations	78	(1)
Analysis of Mutagenesis in Mammalian Cells	79	(6)
Use of Site-Specific Adducts	85	(1)
Replication Fidelity and DNA Polymerase Structure	86	(12)
Templated Information in DNA	86	(1)
Energetics of Base Pairing	87	(1)
Geometric Selection of Nucleotides during DNA Synthesis	87	(3)
A Two-Metal-Ion Mechanism for DNA Synthesis	90	(2)
Open and Closed Conformations of DNA Polymerases	92	(1)
Importance of Base-Pairing Geometry versus Hydrogen Bonds	92	(1)
Selection against Ribonucleotides	93	(1)
Proofreading during DNA Synthesis	93	(2)
Lesion Bypass by Error-Prone DNA Polymerases	95	(3)
Conclusions about Replicative Fidelity	98	(1)
Mechanisms Contributing to Spontaneous Mutagenesis	98	(9)
Base Substitution Mutations Resulting from Misincorporation during DNA Synthesis	98	(1)
Mutations Resulting from Misalignments during DNA Synthesis	99	(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