Note: Cover -- Preface -- Contents -- Volume 1 -- Chapter 1 Biomonitoring of DNA Damage in Humans -- 1.1 Introduction -- 1.2 Methods Used to Monitor DNA Damage in Humans -- 1.2.1 Immunoassays -- 1.2.2 Comet Assay -- 1.2.3 32P-postlabelling -- 1.2.4 Electrochemical Detection (ECD) -- 1.2.5 Mass Spectrometry (MS) -- 1.2.6 Spectroscopic Methods to Detect DNA Adducts -- 1.3 Human Biospecimens for Screening DNA Damage -- 1.3.1 Fresh Tissues -- 1.3.2 Biofluids and Exfoliated Cells -- 1.3.3 FFPE-The Underutilized Biospecimen -- 1.4 Conclusions and Futures Directions -- Acknowledgements -- References -- Chapter 2 Tandem and Clustered Lesions from Radicals in Nucleic Acids from a Single Initial Chemical Event -- 2.1 Introduction -- 2.2 Double-strand Break Formation from a Single C4'-radical -- 2.3 Tandem and Clustered Lesion Formation from Nucleobase Radical Adducts -- 2.3.1 Nucleobase Radical Formation -- 2.3.2 DNA Pyrimidine Nucleobase Radical Reactivity -- 2.3.3 RNA Pyrimidine Nucleobase Radical Reactivity -- 2.4 Tandem Lesion Formation from Pyrimidine Methyl Radicals -- 2.4.1 5-(2'-Deoxyuridinyl)Methyl and 5-(2'-Deoxycytidinyl)Methyl Radical Reactivity -- 2.5 Intrastrand Cross-link Tandem Lesions from Pyrimidine s-Radicals, Hydroxyl Radical Adducts and Radical Cations -- 2.5.1 2'-Deoxycytidine-purine Intrastrand Cross-links -- 2.6 Tandem Lesion Formation from Purine Radicals -- 2.6.1 2'-Deoxyadenosin-N6-yl Radical Formation -- 2.6.2 2'-Deoxyadenosin-N6-yl Radical (68) Reactivity -- 2.6.3 Tandem Lesions from Selective One-electron Oxidation of dG -- 2.7 Summary -- Acknowledgements -- References -- Chapter 3 Oxidative DNA Damage and Repair in G-quadruplexes -- 3.1 Introduction -- 3.2 Guanine Oxidation in DNA -- 3.2.1 Endogenous and Environmental Oxidants -- 3.2.2 Guanine Oxidation Mechanisms and Products -- 3.2.3 Sites of Guanine Oxidation in DNA. , 3.3 DNA Repair of Lesions in G-quadruplex Sequences -- 3.3.1 Overview of the Base Excision Repair Pathway -- 3.3.2 The DNA Structural Dependency for OG Removal by OGG1 -- 3.3.3 Structural Dependency of Lesion Removal from DNA by NEIL Glycosylases -- 3.3.4 Removal of an AP from DNA by APE Is Structure Dependent -- 3.4 Genomic OG Is Epigenetic in the Regulation of Gene Expression -- 3.4.1 Historically, OG Was Proposed to Be Mutagenic -- 3.4.2 Oxidation of G to OG in Specific Gene Promoters Can Induce Transcription -- 3.4.3 Oxidation of G to OG in a Promoter PQS Regulates Transcription -- 3.4.4 OG in Promoter PQSs Can Serve as an On/Off Switch for Transcription -- 3.5 Concluding Remarks -- References -- Chapter 4 Oxidatively Induced DNA Damage: Mechanisms and Measurement -- 4.1 Introduction -- 4.2 Mechanisms of Oxidatively Induced DNA Damage -- 4.2.1 Mechanisms of Damage to Purines -- 4.2.2 Mechanisms of Damage to Pyrimidines -- 4.2.3 Mechanisms of Damage to 2'-Deoxyribose -- 4.2.4 Mechanisms of Formation of Tandem Lesions -- 4.3 Repair of Oxidatively Induced DNA Damage -- 4.4 Biological Effects of Oxidatively Induced DNA Damage -- 4.4.1 Products of DNA Bases -- 4.4.2 Products of 2'-Deoxyribose -- 4.4.3 Tandem Lesions -- 4.5 Measurement of Oxidatively Induced DNA Damage -- 4.5.1 Measurement of the 2'-Deoxyribose Products -- 4.5.2 Measurement of the DNA Base Products -- 4.6 Summary -- References -- Chapter 5 Oxidation of the C5' Position in DNA and the Role of Purine 5',8-Cyclo-2'-deoxynucleoside Lesions -- 5.1 Endogenous Formation of Hydroxyl Radicals and Oxidation of the C5' Position in DNA -- 5.2 Mechanistic Studies of cPu Formation and Synthesis of the cPu Library -- 5.2.1 The Simplest Models -- 5.2.2 Bioinspired Synthesis of cdA and cdG -- 5.2.3 Synthesis of Oligonucleotides Containing Site-specifically Inserted cPu. , 5.3 Quantification of cPu Lesions in DNA -- 5.4 Biological Studies and Identification of cPu Lesions in Cellular and Animal Models -- 5.5 DNA Repair: BER and NER -- 5.6 Biological Effects of cPu on: Replication, Repair and Transcription -- 5.6.1 Incorporation of cPu by DNA Polymerase I -- 5.6.2 Inhibition of Transcription by cPu -- 5.6.3 Alteration of DNA Polymerase Activities by cPu -- 5.7 Summary -- References -- Chapter 6 Ferroptosis and Oxidative DNA Damage -- 6.1 Ferroptosis -- 6.2 Iron, Sulfur and Oxygen in Evolution -- 6.3 Cancer -- 6.4 Oxidative Stress and Cancer -- 6.5 Cancer as Ferroptosis-resistance -- 6.6 Familial Cancer Syndromes -- 6.6.1 BRCA1/2 -- 6.6.2 BAP1 -- 6.6.3 MUTYH -- 6.7 Oxygenomics -- 6.8 Non-thermal Plasma -- 6.9 Conclusion -- Acknowledgements -- References -- Chapter 7 DNA-Protein Cross-links: Formation, Genotoxicity and Repair -- 7.1 Introduction -- 7.2 Mechanism of DPC Formation -- 7.2.1 Enzymatic DPCs -- 7.2.2 Non-enzymatic DPCs -- 7.3 Synthesis of Site-specific DPCs -- 7.4 Replication and Mutagenesis -- 7.4.1 Early Investigations -- 7.4.2 Recent Studies on Replication -- 7.4.3 Effects of DPCs on Helicase Enzymes -- 7.5 Effects of DPCs on Transcription -- 7.6 DPC Repair -- Acknowledgements -- References -- Chapter 8 Substrate Specificities of DNA Glycosylases In Vitro and In Vivo -- 8.1 DNA Glycosylases: An Overview -- 8.2 Deamination Damage Repair -- 8.2.1 The Prototypical DNA Glycosylase: Uracil-DNA Glycosylase -- 8.2.2 SMUG1: More than a Back-up? -- 8.2.3 CpG Guardian: MBD4 -- 8.3 Repair Repurposed: TDG and Mug -- 8.4 Oxidative Damage Repair -- 8.4.1 GO System -- 8.4.2 Oxidized Pyrimidines Repair: Endonuclease III (Nth, NTHL1) -- 8.4.3 Specialized Oxidative Damage Repair: Nei, NEIL1, NEIL2, and NEIL3 -- 8.5 Alkylation Damage Repair: AlkA, Tag and MPG -- 8.6 Dynamic Aspects of Lesion Recognition. , 8.7 Concluding Remarks -- Acknowledgements -- References -- Chapter 9 Special Problems for Base Excision Repair in Coping with Oxidatively-induced DNA Damage -- 9.1 Sources of Endogenous and Oxidatively-induced DNA Damage -- 9.1.1 The Chemical Instability of DNA -- 9.2 Metabolites and Physiological By-products -- 9.2.1 Oxidatively-induced DNA Damage -- 9.2.2 Other DNA-damaging Metabolites -- 9.2.3 Environmental Sources of Oxidatively-induced DNA Damage -- 9.3 Lesions of Oxidatively-induced DNA Damage -- 9.3.1 Base Damage -- 9.3.2 2'-Deoxyribose Damage -- 9.4 A Note on the Frequency of Oxidatively-induced DNA Lesions -- 9.5 Cancer Therapy -- 9.6 Base Excision DNA Repair (BER) -- 9.6.1 DNA Glycosylases -- 9.6.2 AP Endonucleases -- 9.6.3 The DNA Polymerases of BER -- 9.7 Dangerous Lesions -- 9.7.1 2-Deoxyribonolactone -- 9.7.2 Oxanine -- 9.7.3 Hydantoins -- 9.8 Conclusion -- Acknowledgements -- References -- Chapter 10 Genomic Uracil in Biology, Immunity and Cancer -- 10.1 Introduction -- 10.2 Sources of Genomic Uracil -- 10.2.1 Deamination of Cytosine Is Highly Mutagenic -- 10.2.2 Enzymatic Deamination by the APOBEC Family of Deaminases -- 10.2.3 Cellular dUTP, Uracil Misincorporation and Functional Consequences -- 10.3 Enzymatic Processing of Genomic Uracil -- 10.3.1 The UDG Superfamily -- 10.3.2 The Atomic Structure of UNG Proteins Reveals a Highly Tailored Active Site Pocket -- 10.3.3 Mammalian UNG Proteins - Three Isoforms Are Now Known -- 10.3.4 Role of Mammalian Uracil-DNAGlycosylases in BER and DNA Demethylation -- 10.4 Viral UNG Proteins Are Replication Factors and Potential Drug Targets -- 10.5 Fluoropyrimidines Perturb DNA and RNA Functions -- 10.6 Genomic Uracil in Cancer Development -- 10.7 Future Perspectives -- Acknowledgements -- References. , Chapter 11 Alternative DNA Repair Pathways to Handle ComplexDNA Damage Generated by Oxidative Stress and Anticancer Drugs -- 11.1 Chemical Nature of Complex DNA Damage -- 11.1.1 Repair-resistant Bulky DNA Adducts -- 11.1.2 Formation and Chemical Nature of DNA Crosslinks -- 11.2 DNA Glycosylase-mediated Repair of Complex DNA Lesions -- 11.2.1 DNA Glycosylase-mediated Removal of Bulky DNA Lesions -- 11.2.2 DNA Glycosylase-mediated Repair of Inter-strand DNA Crosslinks -- 11.2.3 Aberrant Repair of Interstrand DNA Crosslinks -- 11.3 The Apurinic/Apyrimidinic (AP)Endonuclease-initiated NucleotideIncision Repair Pathway for Oxidative DNA Damage -- 11.3.1 Substrate Specificity of AP Endonucleases as Multifunctional Enzymes -- 11.3.2 A Putative Physiological Role of APE1-catalyzed NIR and 3'→5' Exonuclease Functions -- 11.3.3 Conformational Dynamics of Enzyme-Substrate Complexes -- 11.3.4 The Mechanism of Substrate SpecificityTowards Damaged Nucleotides, with Human APE1 as an Example -- 11.4 Poly( ADP-ribose) Polymerase Catalysed Covalent Modification of DNA Strand Break Extremities and its Role in DNA Repair -- Acknowledgements -- References -- Chapter 12 Redox Stress Responses and Human Disease: NTHL1 at the Intersection of DNA Damage Repair and Cancer -- 12.1 Introduction -- 12.2 Function of ROS under Normal Physiological Conditions -- 12.2.1 ROS Signaling in Response to Environmental Insults -- 12.2.2 Redox Signaling in Regulation of Cellular Metabolism -- 12.2.3 ROS and Aging -- 12.2.4 Role of ROS in Immune Responses -- 12.2.5 Hormesis -- 12.3 Pathophysiology of Redox Stress -- 12.3.1 Cancer -- 12.3.2 Atherosclerosis -- 12.3.3 Neurodegenerative Diseases -- 12.3.4 Diabetes Mellitus -- 12.4 Repair of ROS-induced DNA Damage -- 12.4.1 Base Excision Repair (BER) as the Major Repair Mechanism of Oxidatively-induced DNA Damage. , 12.5 Dysregulation of DNA Glycosylases and Cancer.

Note: Cover -- Preface -- Contents -- Volume 2 -- Chapter 16 Mechanisms and Maps of Nucleotide Excision Repair -- 16.1 Introduction -- 16.2 Mechanisms of NER -- 16.2.1 NER in E. coli -- 16.2.2 Mammalian NER -- 16.3 Mapping DNA Damage and NER -- 16.3.1 Damage-sequencing -- 16.3.2 Excision Repair Sequencing -- 16.4 NER and Disease -- 16.4.1 NER and Tumor Development -- 16.4.2 NER and Tumor Response to Cisplatin -- 16.5 Summary -- References -- Chapter 17 Emerging Concepts on the Early Steps of Base Excision Repair Pathway with a Focus on Gene Expression -- 17.1 Introduction -- 17.2 Roles of Base Excision Repair Pathway in Genome Stability -- 17.2.1 Canonical Function of BER in Repairing Non-bulky DNA Lesions -- 17.2.2 Emerging Role of BER in RNA:DNA Hybrids Processing -- 17.3 Base Excision Repair in Gene Expression Regulation -- 17.3.1 Role of Base Excision Repair in Transcriptional Regulation -- 17.3.2 Novel Role of Base Excision Repair in RNA Processing -- 17.3.3 BER Functional Regulation by Protein Interactomes and Protein Post-translational Modifications -- 17.4 Relevance of RNA Damage and Its Biological Consequences: A Novel Target of BER? -- 17.5 Summary -- Acknowledgements -- References -- Chapter 18 Base Excision Repair in Plants: Variations on a Theme -- 18.1 Introduction -- 18.2 An Overview of the Plant BER Pathway -- 18.2.1 Base Excision -- 18.2.2 Strand Incision -- 18.2.3 Cleaning of DNA Ends -- 18.2.4 Gap Filling -- 18.2.5 DNA Ligation -- 18.3 Common DNA Lesions Repaired by Plant BER -- 18.3.1 Base Alkylation -- 18.3.2 Cytosine Deamination -- 18.3.3 Purine Oxidation -- 18.3.4 Pyrimidine Oxidation -- 18.3.5 Base Loss -- 18.4 Role of Plant BER in Erasing an Epigenetic Mark: 5-Methylcytosine -- 18.4.1 The DML Family of DNA Glycosylases -- 18.4.2 The Active DNA Demethylation Pathway in Plants. , 18.4.3 Biological Roles of BER-mediated DNA Demethylation -- 18.5 Future Perspectives -- References -- Chapter 19 OGG1 at the Crossroads of Inflammation and DNA Base Excision Repair -- 19.1 Introduction -- 19.2 OGG1 and Cellular Control of Its Enzymatic Activities -- 19.3 Accumulation of 8-oxoGua in the Mouse Genome - Lack of Phenotype -- 19.3.1 Increased Resistance to Innate Inflammation in Ogg1 KO Mice -- 19.3.2 Altered Adaptive Immune Responses in Ogg1 KO Mice to Allergens -- 19.4 Genomic 8-oxoGua is an ROS-generated Epigenetic-like Mark -- 19.5 DNA Occupancy of Transcription Factors Is Modulated by OGG1 -- 19.5.1 DNA Allosteric Changes by OGG1 - An Interface for TF Binding -- 19.5.2 OGG1 Nucleates NF-k-B-Driven Chromatin-remodelling -- 19.6 Post-repair Activation of Cell Signaling by OGG1 -- 19.6.1 OGG1 8-oxoGua-KRAS-NF-k-B Pathway - HostImmune Homeostasis -- 19.6.2 OGG1 8-oxoGua-RAS Signaling Facilitates AdaptiveImmune Responses -- 19.7 Active Site Inhibitors of OGG1 Decrease Inflammatory Responses -- 19.8 Conclusion -- Acknowledgements -- References -- Chapter 20 Fidelity Mechanisms of DNA Polymerase Beta -- 20.1 Introduction -- 20.2 Biological Significance of DNA Polymerase -- 20.3 Structural Overview of Pol -- 20.4 Catalytic Mechanism of Pol -- 20.4.1 The Two Metal Ion Mechanism -- 20.4.2 Pre-steady-state Kinetics -- 20.4.3 Use of Nucleotide Analogues to Probe Pol b CatalysisSuggests That the Triphosphate and Base AreImportant for Substrate Specificity -- 20.5 Conformational Movements and Pol -- 20.5.1 Forster Resonance Energy Transfer -- 20.5.2 The Nature of the Primer-Template also Influences Precatalytic Conformational Movements of Pol -- 20.5.3 NMR Characterization Suggests that Dynamic Movements of Pol -- Are Important for Substrate Selection -- 20.6 Structure-function Studies Identify Amino Acid Residues That Are Critical for Catalysis. , 20.6.1 Active Site Residues -- 20.6.2 The Hydrophobic Hinge -- 20.6.3 Human Variants of Pol -- Fidelity -- 20.7 Induced Fit Mechanism of Pol β Fidelity -- 20.7.1 Mutation Assays to Probe Pol -- 20.7.2 Genetic Screens to Identify Mutator Variants of Pol -- 20.7.3 Biophysical Characterization of Mutator Mutants Mapping to the Hydrophobic Hinge Provides Support for the Induced Fit Mec -- 20.7.4 Mutator Mutants Mapping to Helix N Suggest That Flexibility Is Important for Fidelity -- 20.7.5 Threonine 79 Is Important for Stabilization of DNA in the Active Site -- 20.7.6 AZT Resistant Mutants of Pol β Are Unable to Stabilize the DNA -- 20.7.7 Human Variants of Pol β with an Altered Conformation Landscape Exhibit Reduced Fidelity -- 20.7.8 Structural Biology of Infidelity -- 20.8 Summary -- Acknowledgements -- References -- Chapter 21 DNA Damage Leads to Neurodegeneration via Mitochondrial Dysfunction -- 21.1 Introduction -- 21.2 NM Signaling -- 21.2.1 NM Signaling and the Competition for NAD1 -- 21.2.2 NM Signaling - Mitophagy or Cell Death? -- 21.3 mtDNA Repair -- 21.3.1 Base Excision Repair -- 21.3.2 Mismatch Repair -- 21.3.3 Double-strand Break Repair -- 21.3.4 mtDNA Degradation -- 21.4 DNA Damage and Repair in Alzheimer's Disease -- 21.4.1 Alzheimer's Disease and Oxidative DNA Damage -- 21.4.2 BER Polymorphisms and Alzheimer's Disease -- 21.4.3 The Role of Reduced BER Capacity in Alzheimer's Disease -- 21.4.4 DNA Damage and Alzheimer's Disease-like Neurodegeneration -- 21.5 Discussion -- References -- Chapter 22 Emerging Roles of Sirtuins in Chromatin Regulation and DNA Repair via their NAD1-dependent Activities -- 22.1 Introduction -- 22.2 Regulation of BER by the Nucleosome Core Particle -- 22.3 Role of SIRT1 and SIRT6 in Regulating BER -- 22.4 Role of Nucleosome Occupancy in Mutation Rates -- 22.5 Conclusions and Perspectives -- Acknowledgements. , References -- Chapter 23 Unique Roles of Human Translesion Synthesis DNA Polymerase -- 23.1 Introduction -- 23.1.1 Nucleic Acid Damage and the Biological Consequences -- 23.1.2 Ribonucleotide-induced Genomic Instability -- 23.1.3 Ribonucleotide Excision Repair -- 23.1.4 Translesion Synthesis (TLS) -- 23.2 Human TLS Polymerase -- 23.2.1 Mutational Signatures -- 23.2.2 Bypass Studies -- 23.2.3 Scope of the Chapter -- mediated Ribonucleotide Incorporation -- 23.3 hPol η-mediated Ribonucleotide Incorporation -- 23.3.1 hPol η-mediated Ribonucleotide Insertion Opposite CPD and 8-oxo-dG Lesions -- 23.3.2 Crystal Structures of hPol η-with Incoming rNTPs Opposite 8-oxo-dG and CPD Lesions -- 23.4 hPol η Accommodates an RNA Strand -- 23.4.1 hPol η Accommodates an RNA Strand as a Primer Opposite 8-oxo-dGand CPD-containing DNA Templates -- 23.4.2 hPol η Accommodates an RNA Strand as a Template: Reverse Transcription -- 23.5 hPol η Can Act as a Reverse Transcriptase in Human Cells -- 23.5.1 Ribonucleotide Incorporation and Its Repair Opposite a CPD Lesion -- 23.5.2 hPol η Catalyzes the Incorporation of rNTPs Oppositea CPD Lesion in Fibroblast Cell Extracts -- 23.5.3 hPol η Acts as a Reverse Transcriptase in Human CellExtracts -- 23.6 Ribonucleotide Tolerance and Reverse Transcription by hPol η -- 23.6.1 hPol η Generates Frameshifts in the Bypass of 1,N6-εrA -- 23.6.2 Human RNase H2 and E. coli RNase HII-mediated Repair of 1,N6-εrA -- 23.7 Prospects -- 23.8 Summary -- Acknowledgements -- References -- Chapter 24 Replicative and Transcriptional Bypass of Alkylated DNA Lesions in Human Cells -- 24.1 Introduction -- 24.2 Replicative Bypass of Alkylated DNA Lesions in Human Cells -- 24.2.1 Methods -- 24.2.2 Major-groove O6-Alkyl-dG Lesions -- 24.2.3 Major-groove O4-Alkyl-dT Lesions -- 24.2.4 Minor-groove O2-Alkyl-dT Lesions -- 24.2.5 Minor-groove N2-Alkyl-dG Lesions. , 24.3 Transcriptional Bypass of Alkylated DNA Lesions in Human Cells -- 24.3.1 Methods -- 24.3.2 Introduction to Transcriptional Alterations Induced by Alkylated DNA Lesions -- 24.3.3 Transcriptional Bypass and Mutagenesis -- 24.3.4 Transcription-coupled NER and Direct Removal of Alkylated DNA Lesions -- 24.4 Conclusions -- References -- Chapter 25 Mutational Spectra Provide Insight into the Mechanisms Bridging DNA Damage to Genetic Disease -- 25.1 Introduction -- 25.1.1 Mutagenesis - A Ubiquitous Phenomenon -- 25.1.2 Origins and Types of Mutagenesis -- 25.2 Molecular Mechanisms of Mutagenesis -- 25.2.1 Mutational Processes -- 25.2.2 DNA Damage and Lesion Formation -- 25.2.3 DNA Repair of Lesions -- 25.2.4 DNA Replication across a Lesion -- 25.3 Mutational Signatures of Human Cancers -- 25.3.1 Background -- 25.3.2 Mutational Signatures of Exogenous Carcinogens -- 25.3.3 Mutational Signatures Associated with Enzymatic DNA Damage -- 25.3.4 Mutational Signatures Associated with DNA Repair Deficiencies -- 25.3.5 Mutational Signatures of (Currently) Unknown Origin -- 25.3.6 Limitations of Computational Approaches to Uncover Mutational Signatures -- 25.4 Mutational Spectra of Select Carcinogens -- 25.4.1 Aflatoxin B1 -- 25.4.2 Tobacco Smoking -- 25.4.3 Aristolochic Acid -- 25.4.4 Methylating Agents -- 25.5 Summary and Concluding Remarks -- Acknowledgements -- References -- Chapter 26 Evolving DNA Repair Targets for Cancer Therapy -- 26.1 Introduction -- 26.2 Poly ADP Ribose Polymerase Inhibitors (PARPi) -- 26.2.1 PARP1 Inhibition and BRCA -- 26.2.2 Ovarian Cancer (OC) -- 26.2.3 Breast Cancer (BC) -- 26.2.4 Pancreatic Cancer (PC) -- 26.2.5 Prostate Cancer -- 26.3 Ataxia Telangiectasia and Rad3-related (ATR) -- 26.3.1 ATR Signalling -- 26.3.2 Ataxia Telangiectasia-mutated (ATM) Signalling -- 26.3.3 ATR Inhibitor Monotherapy. , 26.3.4 ATR Inhibitor Combinations.