DescriptionBringing the power of biochemical analysis to toxicology, this modern reference explains genotoxicity at the molecular level, showing the links between a DNA lesion and the resulting cellular or organismic response. Clearly divided into two main sections, Part 1 focuses on selected examples of important DNA lesions and their biological impact, while the second part covers current advances in assessing and predicting the genotoxic effects of chemicals, taking into account the biological responses mediated by the DNA repair, replication and transcription machineries.
A ready reference for biochemists, toxicologists, molecular and cell biologists, and geneticists seeking a better understanding of the impact of chemicals on human health.
List of Contributors.
PART ONE Chemistry and Biology of DNA Lesions.
1 Introduction and Perspectives on the Chemistry and Biology of DNA Damage (Nicolas E. Geacintov and Susan Broyde).
1.1 Overview of the Field.
1.2 DNA Damage–A Constant Threat.
1.3 DNA Damage and Disease.
1.4 DNA Damage and Chemotherapeutic Applications.
1.5 The Cellular DNA Damage Response (DDR).
1.6 Repair Mechanisms that Remove DNA Lesions.
1.7 Relationships between the Chemical, Structural, and Biological Features of DNA Lesions.
2 Chemistry of Inflammation and DNA Damage: Biological Impact of Reactive Nitrogen Species (Michael S. DeMott and Peter C. Dedon).
2.2 DNA Oxidation and Nitration.
2.3 DNA Deamination.
2.4 2'-Deoxyribose Oxidation.
2.5 Indirect Base Damage Caused by RNS.
3 Oxidatively Generated Damage to Isolated and Cellular DNA (Jean Cadet, Thierry Douki and Jean-Luc Ravanat).
3.2 Single Base Damage.
3.3 Tandem Base Lesions.
3.4 Hydroxyl Radical-Mediated 2-Deoxyribose Oxidation Reactions.
3.5 Secondary Oxidation Reactions of Bases.
3.6 Conslusions and Perspectives.
4 Role of Free Radical Reactions in the Formation of DNA Damage (Vladimir Shafirovich and Nicholas E. Geacintov).
4.2 Importance of Free Radical Reactions with DNA.
4.3 Mechanisms of Product Formation.
4.4 Biological Implications.
5 DNA Damage Caused by Endogenously Generated Products of Oxidative Stress (Charles G. Knutson and Lawrence J. Marnett).
5.1 Lipid Peroxidation.
5.2 2'-Deoxyribose Peroxidation.
5.3 Reactions of MDA and ß-Substituted Acroleins with DNA Bases.
5.4 Stability of M1dG: Hydrolytic Ring-Opening and Reaction with Nucleophiles.
5.5 Propano Adducts.
5.6 Etheno Adducts.
5.7 Mutagenicity of Peroxidation-Derived Adducts.
5.8 Repair of DNA Damage.
5.9 Assessment of DNA Damage.
6 Polycyclic Aromatic Hydrocarbons: Multiple Metabolic Pathways and the DNA Lesions Formed (Trevor M. Penning).
6.2 Radical Cation Pathway.
6.3 Diol Epoxides.
6.4 PAH o-Quinones.
6.5 Future Directions.
7 Aromatic Amines and Heterocyclic Aromatic Amines: From Tobacco Smoke to Food Mutagens. (Robert J. Turesky)
7.2 Exposure and Cancer Epidemiology.
7.3 Enzymes of Metabolic Activation and Genetic Polymorphisms.
7.4 Reactivity of N-Hydroxy-AAs and N-Hydroxy-HAAs with DNA.
7.5 Synthesis of AA-DNA and HAA-DNA Adducts.
7.6 Biological Effects of AA-DNA and HAA-DNA Adducts.
7.7 Bacterial Mutagenesis.
7.8 Mammalian Mutagenesis.
7.9 Mutagenesis in Transgenic Rodents.
7.10 Genetic Alterations in Oncogenes and Tumor Suppressor Genes.
7.11 AA-DNA and HAA-DNA Adduct Formation in Experimental Animals and Methods of Detection.
7.12 AA-DNA and HAA-DNA Adduct Formation in Humans.
7.13 Future Directions.
8 Genotoxic Estrogen Pathway: Endogenous And Equine Estrogen Hormone Replacement Theory (Judy L. Bolton and Gregory R.J. Thatcher).
8.1 Risks of Estrogen Exposure.
8.2 Mechanisms of Estrogen Carcinogenesis.
8.3 Estrogen Receptor as a Trojan Horse (Combined Hormonal/Chemical Mechanism).
8.4 Conclusions and Future Directions.
PART TWO New Frontiers and Challenges: Understanding Structure-Function Relationships and Biological Activity.
9 Interstrand DNA Cross-Linking 1,N2-Deoxyguanosine Adducts Derived From a, ß-Unsatruated Aldehydes: Structure-Function Relationships (Michael P. Stone, hai Huang, Young-Jin Cho, Hye-Young Kim, Ivan D. Kozekov, Albena Kozekova, Hao Wang, Irina G.Minko, R. Stephen Lloyd, Thomas M. Harris and Carmelo J. Rizzo).
9.2 Interstrand Cross-Linking Chemistry of the ?-OH-PdG Adduct (9).
9.3 Interstrand Cross-Linking by the a-CH3-?-OH-PG Adducts Derived from Crotonaldehyde.
9.4 Interstrand Cross-Linking by 4-HNE.
9.5 Carbinolamine Cross-Links Maintain Watson-Crick Base-Pairing.
9.6 Role of DNA Sequence.
9.7 Role of Stereochemistry in Modulating Cross-Linking.
9.8 Biological Significance.
10 Structure-Function Characteristics of Aromatic Amine-DNA Adducts (Bongsup Cho).
10.2 Major Conformational Motifs.
10.3 Conformational Heterogeneity.
10.4 Structures of DNA Lesion-DNA Polymerase Complexes.
11 Mechanisms of Base Excision Repair and Nucleotide Excision Repair (Orlando D. Schärer and Arthur J. Campbell).
11.1 General Features of Base Excision and Nucleotide Excision Repair.
12 Recognition and Removal of Bulky DNA Lesions by the Nucleotide Excision Repait System (Yuqin Cai,Konstantin Kropachev, Marina Kolbanovskiy, Alwxander Kobanovskiy, Suse Broyde, Dinshaw J. Patel and Nicholas E. Geacintov).
12.2 Overview of Mammalian NER.
12.3 Prokaryotic NER.
12.4 Recognition of Bulky Lesions by Mammalian NER Factors.
12.5 Bipartite Model of Mammalian NER and the Multipartite Model of Lesion Recognition.
12.6 DNA Lesions Derived from the Reactions of PAH Diol Epoxides with DNA are Excellent Substrates for Probing the Mechanisms of NER.
12.7 Multidisciplinary Approach Towards Investigating Structure-Function Relationships in the NER of Bulky PAH-DNA Adducts.
12.8 Dependence of DNA Adduct Conformations and NER on PAH Topology and Stereochemistry.
12.9 Dependence of NER of the 10S (+)-trans-anti-B[a]P-N2-dG Adduct on Base Sequence Contexts.
13 Impact of Chemical Adducts on Translesion Synthesis in Replicative and Bypass DNA Polymerases: From Structure to Function (Robert L. Eoff, Martin Egli and F. Peter Guengerich).
13.2 Bypass of Abasic Sites.
13.3 Lesions Generated by Oxidative Damage to DNA.
13.4 Exocyclic DNA Adduct Bypass.
13.5 Alkylated DNA.
13.6 Polycyclic Aromatic Hydrocarbons and the Effect of Adduct Size upon Polymerase Catalysis.
13.7 Cyclobutane Pyrimidine Dimers and UV Photoproducts.
13.8 Inter- and Intrastrand DNA Cross-Links.
14 Elucidating Structure-Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases (Suse Broyde, Lihua Wang, Dinshaw J. Patel and Nicholas E. Geacintov).
14.2 Benzo[a]pyrene-Derived DNA Lesions as a Useful Model.
14.3 Computational Elucidation of the Structural Properties of B[a]P-Derived DNA Lesions in Solution.
14.4 DNA Polymerase Structure-Function Relationships Elucidated with B[a]P-Derived Lesions.
14.5 Mechanism of the Nucleotidyl Transfer Reaction.
14.6 Conclusions and Future Perspectives.
15 Translesion Synthesis and Mutagenic Pathways in Escherichia Coli Cells (Sushil Chandani and Edward L. Loechler).
15.2 Mutagenesis in E. coli has Illuminated Our Understanding of Mutagenesis in General.
15.3 Why Does E. coli have Three Translesion Synthesis DNA Polymerases?
15.4 Overview of the Steps Leading to Translesion Synthesis.
15.5 Case Studies: AAF-C8-dG and N2-dG Adducts, Such as +BP.
15.6 Structure-Function Analysis of Y-Family Pols IV and V of E. coli.
15.7 Y-Family DNA Polymerase Mechanistic Steps.
15.8 Structure of B-Family Pol II of E. coli.
16 Insight into the Molecular Mechanism of Translesion DNA Synthesis in Human Cells Using Probes with Chemically Defined DNA Lesions (Zvi Livneh).
16.2 Overview of TLS.
16.3 Plasmid Model Systems with Defined Lesions for Studying TLS.
16.4 Gap-Lesion Plasmid Assay for Mammalian TLS.
16.5 Some Lesions are Bypassed Most Effectively and Most Accurately by Specific Cognate TLS DNA Polymerases.
16.6 Pivotal Role for Pol ? in TLS Across a Wide Variety of DNA Lesions.
16.7 Knocking-Down the Expression of TLS Polymerases using Small Interfering RNA Provides a useful Tool for the Analysis of TLS using the Gapped Plasmid Assay.
16.8 Evidence that TLS Occurs by Two-Polymerase Mechanisms, in Combinations that Determine the Accuracy of the Process.
17 DNA Damage and Transciption Elongation: Consequences and RNA Integrity (Kristian Dreij, John A. burns, Alexandra Dimitri, Lana Nirenstein, Taissia Noujnykh, David A. Scicchitano).
17.2 DNA Repair.
17.3 Transcription Elongation and DNA Damage.
17.4 RNA Polymerases: A Brief Overview.
17.5 RNA Polymerase Elongation Past DNA Damage.