The Chemical Biology of DNA Damage E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 923

Veröffentlichungsjahr: 2011

Beschreibung

Bringing 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.

Leseprobe

Contents

Preface

List of Contributors

Part One Chemistry and Biology of DNA Lesions

1 Introduction and Perspectives on the Chemistry and Biology of DNA Damage

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

2.1 Introduction

2.2 DNA Oxidation and Nitration

2.3 DNA Deamination

2.4 2'-Deoxyribose Oxidation

2.5 Indirect Base Damage Caused by RNS

2.6 Conclusions

3 Oxidatively Generated Damage to Isolated and Cellular DNA

3.1 Introduction

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 Conclusions and Perspectives

4 Role of Free Radical Reactions in the Formation of DNA Damage

4.1 Introduction

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

5.1 Lipid Peroxidation

5.2 2′-Deoxyribose Peroxidation

5.3 Reactions of MDA and β-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

5.10 Conclusions

6 Polycyclic Aromatic Hydrocarbons: Multiple Metabolic Pathways and the DNA Lesions Formed

6.1 Introduction

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

7.1 Introduction

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 Syntheses 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 Therapy

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 α,β-Unsaturated Aldehydes: Structure–Function Relationships

9.1 Introduction

9.2 Interstrand Cross-Linking Chemistry of the γ-OH-PdG Adduct (9)

9.3 Interstrand Cross-Linking by the α-CH3-γ-OH-PdG 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

9.9 Conclusions

10 Structure–Function Characteristics of Aromatic Amine-DNA Adducts

10.1 Introduction

10.2 Major Conformational Motifs

10.3 Conformational Heterogeneity

10.4 Structures of DNA Lesion-DNA Polymerase Complexes

10.5 Conclusions

11 Mechanisms of Base Excision Repair and Nucleotide Excision Repair

11.1 General Features of Base Excision and Nucleotide Excision Repair

11.2 BER

11.3 NER

11.4 Conclusions

12 Recognition and Removal of Bulky DNA Lesions by the Nucleotide Excision Repair System

12.1 Introduction

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 Context

12.10 Conclusions

13 Impact of Chemical Adducts on Translesion Synthesis in Replicative and Bypass DNA Polymerases: From Structure to Function

13.1 Introduction

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 ofAdduct Size upon Polymerase Catalysis

13.7 Cyclobutane Pyrimidine Dimers and UV Photoproducts

13.8 Inter- and Intrastrand DNA Cross-Links

13.9 Conclusions

14 Elucidating Structure–Function Relationships in Bulky DNA Lesions: From Solution Structures to Polymerases

14.1 Introduction

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

15.1 Introduction

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 [126, 127]?

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

16.1 Introduction

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 ζ 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

16.9 Conclusions

17 DNA Damage and Transcription Elongation: Consequences and RNA Integrity

17.1 Introduction

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

17.6 Conclusions

Index

Further Reading

Nakamoto, K., Tsuboi, M., Strahan, G. D.

Drug-DNA Interactions

Structures and Spectra

2009

Hardcover

ISBN: 978-0-471-78626-9

Singleton, P.

Dictionary of DNA and Genome Technology

2008

Hardcover

ISBN: 978-1-4051-5607-3

Müller, S. (ed.)

Nucleic Acids from A to Z

A Concise Encyclopedia

2008

Hardcover

ISBN: 978-3-527-31211-5

Matta, C. F. (ed.)

Quantum Biochemistry

2 Volumes

2010

Hardcover

ISBN: 978-3-527-32322-7

Ekins, S. (ed.)

Computational Toxicology

Risk Assessment for Pharmaceutical and Environmental Chemicals

2007

Hardcover

ISBN: 978-0-470-04962-4

O’Brien, P. J., Bruce, W. R. (eds.)

Endogenous Toxins

Targets for Disease Treatment and Prevention

2010

Hardcover

ISBN: 978-3-527-32363-0

The Editors

Prof. Nicholas E. Geacintov

New York University Chemistry Department 31 Washington Place New York, NY 10003 USA

Prof. Suse Broyde

New York University Department of Biology 100 Washington Square New York, NY 10003 USA

Cover

The cover art is based on the modeling work of Dr. Lei Jia (Nucleic Acids Research, Volume 36, pages 6571-6584 (2008), and with assistance in rendering from Dr. Lihua Wang and Dr. Yuqin Cai, as well as Dr. Martin Graf (Wiley-VCH).

It shows DNA damaged by the environmental chemical carcinogen benzo[a]pyrene in the active site of the human DNA bypass polymerase κ.

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.

© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

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Preface

The relationships between the chemical, structural, and biological aspects of DNA damage have long been parallel and overlapping research domains. More recently, interest has intensified in relating the structural characteristics of DNA damage with its ultimate manifestation – the development of human disease. New opportunities for moving the field forward and for gaining a better understanding of the molecular basis of diseases associated with DNA damage are emerging. Rapid advances in instrumentation and computing power are yielding new structural information on macromolecular biological systems and assemblies through high-resolution structural studies at the molecular level. The subject of this book, the chemical biology of DNA damage, offers the opportunity for considering DNA damage from the molecular perspective with a focus on both the chemical elements at the level of damage generation and the biological properties of the various types of damage from the structure-function points of view.

The topics covered in this book should be of interest to researchers who wish to gain an overview of the frontier areas of the field, as well as to students who wish to learn or deepen their knowledge in areas that touch on the molecular origins of disease via DNA damage. Another objective of this book is to foster communication between the chemical and biological communities of researchers by highlighting the molecular origins that unite these topics at a fundamental level. The time is ripe for promoting such a fundamental understanding since new information on the biological impact of chemically defined lesions is now becoming available at an increasing pace.

This book is divided into two parts. The focus of Part One is on the chemical aspects of DNA damage, while the emphasis of Part Two is on the structural and functional relationships of DNA lesions, and their processing by the cellular machineries of repair, replication, and transcription. Chapter 1 in Part One is intended as a brief overview of the vast field of DNA damage, and introduces the reader to the relationships between the chemical and structural aspects of DNA damage, and some of the known biological endpoints and correlations with human disease. Ample references are provided with an emphasis on authoritative, recently published reviews to guide the interested reader.

The two parts of this book, the chemical and the biological components, spring from the same tree and feed from the same roots – the chemical and structural features of DNA lesions that after the normal structural features of the DNA molecule. If these lesions are not removed by cellular DNA repair mechanisms, DNA replication may be either inhibited entirely or occur in an error-prone manner with dire consequences for the cell. The molecular events underlying these phenomena are at the intersections of the chemical and biological disciplines at the frontiers of our current knowledge. It is our belief that a deeper understanding of the connections between these disciplines will lead to more effective strategies for preventing disease and to advanced therapeutic approaches for treating diseases such as human cancers.

New York, April 2010

Nicholas E. Geacintov Suse Broyde

List of Contributors

Judy L. Bolton

University of Illinois at Chicago

College of Pharmacy

Department of Medicinal Chemistry

and Pharmacognosy (M/C 781)

833 S. Wood Street

Chicago, IL 60612-7231

USA

Suse Broyde

New York University

Department of Biology

100 Washington Square East

New York, NY 10003-6688

USA

John A. Burns

New York University

Department of Biology

100 Washington Square East

New York, NY 10003-6688

USA

Jean Cadet

CEA/Grenoble

Laboratoire “Lésions des Acides

Nucléiques”

SCIB-UMR-E No. 3 (CEA/UJF)

Institut Nanosciences et Cryogénie

17 avenue des Martyrs, 38054

Grenoble Cedex 9

France

Université de Sherbrooke

Faculté de médecine et des sciences

de la santé

Département de médecine nucléaire et

radiobiologie

3001, 12e Avenue Nord, Sherbrooke,

Québec

Canada J1H5N4

Yuqin Cai

New York University

Department of Biology

100 Washington Square East

New York, NY 10003-6688

USA

ArthurJ. Campbell

Stony Brook University

Department of Chemistry

Graduate Chemistry Building

Stony Brook, NY 11794-3400

USA

Sushil Chandani

Boston University

Biology Department

5 Cummington Street

Boston, MA 02215

USA

Bongsup Cho

University of Rhode Island

Biomedical and Pharmaceutical Sciences

41 Lower College Road

Kingston, RI 02881

USA

Young-Jin Cho

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Peter C. Dedon

Massachusetts Institute of Technology

Department of Biological Engineering

Center for Environmental Health Sciences

77 Massachusetts Avenue

Cambridge, MA 02139

USA

Michael S. DeMott

Massachusetts Institute of Technology

Department of Biological Engineering

77 Massachusetts Avenue

Cambridge, MA 02139

USA

Alexandra Dimitri

New York University

Department of Biology

1009 Silver Center, 100 Washington Square East

New York, NY 10003-6688

USA

Thierry Douki

CEA/Grenoble

Laboratoire “Lésions des Acides Nucléiques”

SCIB-UMR-E No. 3 (CEA/UJF)

Institut Nanosciences et Cryogénie

17 avenue des Martyrs, 38054

Grenoble Cedex 9

France

Kristian Dreij

New York University

Department of Biology

1009 Silver Center, 100 Washington Square East

New York, NY 10003-6688

USA

Martin Egli

Vanderbilt University School of Medicine

Department of Biochemistry and Molecular Toxicology Center

2200 Pierce Avenue

Nashville, TN 37232-0146

USA

Robert L. Eoff

Vanderbilt University School of Medicine

Department of Biochemistry and Molecular Toxicology Center

2200 Pierce Avenue

Nashville, TN 37232-0146

USA

Nicholas E. Geacintov

New York University

Chemistry Department

31 Washington Place

New York, NY 10003-5180

USA

F. Peter Guengerich

Vanderbilt University School of Medicine

Department of Biochemistry and Molecular Toxicology Center

2200 Pierce Avenue

Nashville, TN 37232-0146

USA

Thomas M. Harris

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Hai Huang

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Hye-Young Kim

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Charles G. Knutson

Vanderbilt University School of Medicine

A.B. Hancock Jr. Memorial Laboratory for Cancer Research

Departments of Biochemistry, Chemistry, and Pharmacology

Vanderbilt Institute of Chemical Biology

Center in Molecular Toxicology

Vanderbilt-Ingram Cancer Center

2220 Pierce Avenue

Nashville, TN 37232-1046

USA

Alexander Kolbanovskiy

New York University

Department of Chemistry

31 Washington Place

New York, NY 10003-5180 USA

Marina Kolbanovskiy

New York University

Department of Chemistry

31 Washington Place

New York, NY 10003-5180

USA

Ivan D. Kozekov

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Albena Kozekova

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology

Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Konstantin Kropachev

New York University

Department of Chemistry

31 Washington Place

New York, NY 10003-5180

USA

Zvi Livneh

Weizmann Institute of Science

Department of Biological Chemistry

PO Box 26, Rehovot 76100

Israel

R. Stephen Lloyd

Oregon Health & Science University

Center for Research on Occupational and Environmental Toxicology

3181 SW Sam Jackson Park Road

Portland, OR 97239-3098

USA

Edward L. Loechler

Boston University Biology

Department 5 Cummington Street

Boston, MA 02215

USA

LawrenceJ. Marnett

Vanderbilt University School of Medicine

A.B. Hancock Jr. Memorial Laboratory for Cancer Research

Departments of Biochemistry, Chemistry, and Pharmacology,

Vanderbilt Institute of Chemical Biology

Center in Molecular Toxicology

Vanderbilt-Ingram Cancer Center

2220 Pierce Avenue

Nashville, TN 37232-1046

USA

Irina G. Minko

Oregon Health & Science University

Center for Research on Occupational and Environmental Toxicology

3181 SW Sam Jackson Park Road

Portland, OR 97239-3098

USA

Lana Nirenstein

New York University

Department of Biology

1009 Silver Center, 100 Washington

Square East

New York, NY 10003-6688

USA

Taissia Noujnykh

New York University

Department of Biology

1009 Silver Center, 100 Washington Square East

New York, NY 10003-6688

USA

DinshawJ. Patel

Memorial Sloan-Kettering Cancer Center

Structural Biology Program

1275 York Avenue

New York, NY 10065

USA

Trevor M. Penning

University of Pennsylvania

School of Medicine

Centers of Excellence in Environmental Toxicology and Cancer Pharmacology

Department of Pharmacology

3620 Hamilton Walk

Philadelphia, PA 19104-6084

USA

Jean-Luc Ravanat

CEA/Grenoble

Laboratoire “Lésions des Acides Nucléiques”

SCIB-UMR-E No. 3 (CEA/UJF)

Institut Nanosciences et Cryogénie

17 avenue des Martyrs, 38054

Grenoble Cedex 9

France

Carmelo J. Rizzo

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology, Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Orlando D. Schärer

Stony Brook University

Departments of Pharmacological Sciences and Chemistry

Graduate Chemistry Building

Stony Brook, NY 11794-3400

USA

David A. Scicchitano

New York University

Department of Biology

100 Washington Square East

New York, NY 10003-6688

USA

Vladimir Shafirovich

New York University

Chemistry Department

31 Washington Place

New York, NY 10003-5180

USA

Michael P. Stone

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology, Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Gregory R.J. Thatcher

University of Illinois at Chicago

College of Pharmacy

Department of Medicinal Chemistry and Pharmacognosy (M/C 781)

833 S. Wood Street

Chicago, IL 60612-7231

USA

Robert J. Turesky

Wadsworth Center

Division of Environmental Health Sciences

Empire State Plaza

Albany, NY 12201

USA

Hao Wang

Vanderbilt University

Center in Molecular Toxicology, and the Vanderbilt Institute for Chemical Biology, Department of Chemistry

1211 Medical Center Drive

Nashville, TN 37235

USA

Lihua Wang

New York University

Biology Department

100 Washington Square East

New York, NY 10003 - 6688

USA

Part One

Chemistry and Biology of DNA Lesions

1

Introduction and Perspectives on the Chemistry and Biology of DNA Damage

Nicholas E. Geacintov and Suse Broyde

1.1 Overview of the Field

The subject of this book, the chemical biology of DNA damage, is concerned with the chemistry that produces DNA damage, and the relationships between the structural features of the DNA lesions formed and their biological impact. The subjects and examples described illustrate the interdisciplinary approaches that can be used to bridge the gaps between the chemical aspects and biological end-points of DNA damage, especially lesions generated by different endogenous and exogenous DNA-damaging agents. In Part One (Chapters 2–8), the focus is on the chemistry and biological impact of some representative and important DNA lesions. The topics of Part Two (Chapters 9–17) deal with recent and current research on the relationships between the chemical structure and physical properties of selected DNA lesions, and how the lesions are processed by the DNA repair, replication, and transcription machineries.

The chemistry of DNA damage is complex and the variety of DNA lesions is enormous. This book considers an important subset of DNA lesions that illustrate the relationships between the chemistry, structure, biochemistry, and biology of DNA damage. In this chapter, we provide a broad but brief overview of this vast field. Some of the established links between DNA damage and human diseases are highlighted. The objectives of this chapter are to situate the topics covered in this book within the overall field and to guide the interested reader to the original literature concerned with topics that either are or are not explicitly covered in the rest of the book.

We begin with an overview of the origins of DNA damage, followed by summaries of the relationships between DNA lesions and disease, and a brief overview of cellular DNA damage response (DDR) systems, and conclude with a brief description of the specific topics covered in this book and how they relate to the field overall.

1.2 DNA Damage–A Constant Threat

The human genome is under constant attack from endogenous and exogenous reactive chemical species. A variety of genotoxic agents can induce chemical transformation of the nucleotides or damage the phosphodiester backbone of DNA with deleterious consequences for the cell. The relationships between cellular DNA damage caused by endogenous and environmental genotoxic agents, the cellular response, and the development and prevention of human diseases and aging are areas of great current interest in the medical, biological, and chemical research communities [1].

It has been estimated that there are tens of thousands of DNA-damaging events per day suffered by the approximately 1013 cells within the human body [2] and that DNA damage associated with endogenous species is more extensive (greater than 75%) than damage caused by environmental factors [3]. Among the endogenous species that damage cellular DNA are reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive intermediates are produced under conditions of oxidative stress, a consequence of normal metabolic activity, and the inflammatory response [3, 4]. Other forms of endogenous DNA damage are depu-rination (and to a lesser extent depyrimidination) that arise from the hydrolysis of the glycosidic bonds between the nucleobase and deoxyribose residues, thus leading to the formation of apurinic (or apyrimidinic) sites [5]. The hydrolytic deamination of cytosine can also occur spontaneously and give rise to uracil [6]. Both forms of DNA damage, if not repaired by the normally efficient cellular base excision repair (BER) mechanism, can result in the mutagenic insertion of an incorrect base during error-prone translesion synthesis when the DNA is replicated past the lesion.

Among the external causes of DNA damage are ionizing radiation and solar UV radiation. Sunlight has been called the most prominent and ubiquitous physical carcinogen in our natural environment [7]. There are ample epidemiological data and a wealth of supporting animal model experiments that indicate that solar UV radiation is a major cause of skin cancer among the white Caucasian populations in the Western world [8]. The UV portion of the solar spectrum in the 290- to 300-nm region is absorbed by DNA and forms cyclobutane pyrimidine dimers (CPDs) that have been linked to the etiology of skin cancer [9]. Ionizing radiation is routinely used in medical diagnostic and chemotherapeutic applications. There are different forms of radiation that generate a variety of DNA lesions that include double- and single-strand breaks, as well as oxidatively modified nucleobases and deoxyribose moieties. The human population is also continuously exposed to environmental pollutants that are present in air, water, and food [10]. Many of these chemicals are metabolized in human cells to highly reactive intermediates that react chemically with the nucleobases to form deleterious DNA strand breaks and a variety of DNA lesions or adducts that are readily detectable in human cells [11–13]. Fortunately, nature has devised a host of cellular defense or DNA repair mechanisms that have been described [14] and reviewed in a comprehensive monograph [15]. Some of the mechanisms that involve the removal of DNA lesions are discussed in Chapters 11 and 12. The effects of DNA lesions that escape repair can be bypassed during DNA replication by a damage tolerance mechanism that depends on the actions of a set of specialized polymerases [16, 17] or through homologous recombination mechanisms that leave the lesion intact on the damaged strand [18].