Preface ........................................................ XV
List of Contributors ......................................... XVII
Part One Chemistry and Biology of DNA Lesions ................ 1
1 Introduction and Perspectives on the Chemistry and Biology
of ONA Damage ................................................ 3
Nicholas E. Geacintov and Suse Broyde
1.1 Overview of the Field ................................... 3
1.2 DNA Damage-A Constant Threat ............................ 4
1.3 DNA Damage and Disease .................................. 5
1.3.1 The Inflammatory Response ........................ 5
1.3.2 Reactive Oxygen and Nitrogen Species ............. 5
1.3.3 Early Recognition of Environmentally Related
Cancers: Polycyclic Aromatic Hydrocarbons ........ 6
1.3.4 Exposure to Environmental Cancer-Causing
Substances ....................................... 6
1.3.5 Anatoxins ........................................ 7
1.3.6 Aristolochic Acid ................................ 7
1.3.7 Estrogens ........................................ 8
1.4 DNA Damage and Chemotherapeutic Applications ............ 8
1.5 The Cellular DNA Damage Response (DDR) .................. 9
1.6 Repair Mechanisms that Remove DNA Lesions .............. 10
1.6.1 Repair of Single-and Double-Strand Breaks ....... 10
1.6.2 Alkylating Agents ............................... 10
1.6.3 Base Excision Repair ............................ 11
1.6.4 Mismatch Excision Repair ........................ 11
1.6.5 Nucleotide Excision Repair ...................... 11
1.6.6 Translesion Bypass of Unrepaired Lesions by
Specialized DNA Polymerases and RNA
Polymerases ..................................... 12
1.7 Relationships between the Chemical, Structural, and
Biological Features of DNA Lesions ..................... 12
Acknowledgements ....................................... 15
References .................................................. 15
2 Chemistry of Inflammation and DNA Damage: Biological
Impact of Reactive Nitrogen Species ......................... 21
Michael S. DeMott and Peter C. Dedon
2.1 Introduction ........................................... 21
2.2 DNA Oxidation and Nitration ............................ 23
2.2.1 Spectrum of Guanine Oxidation Products Caused
by ONOO-, ONOOCO2-, and NO2• ..................... 23
2.2.2 Base Oxidation Products as Biomarkers of
Inflammation and Oxidative Stress ............... 25
2.2.3 Charge Transfer as a Determinant of the
Location of G Oxidation Products in DNA ......... 25
2.3 DNA Deamination ........................................ 26
2.3.1 Problem of Oxanine .............................. 29
2.3.2 Analytical Methods and Artifacts ................ 29
2.4 2'-Deoxyribose Oxidation ............................... 30
2.4.1 Variation of 2'-Deoxyribose Oxidation
Chemistry as a Function of the Oxidant .......... 34
2.5 Indirect Base Damage Caused by RNS ..................... 35
2.5.1 Malondialdehyde and Related Adducts ............. 37
2.6 Conclusions ............................................ 38
Acknowledgements ....................................... 38
References ............................................. 38
3 Oxidatively Generated Damage to Isolated and Cellular DNA ... 53
Jean Cadet, Thierry Douki, and Jean-Luc Ravanat
3.1 Introduction ........................................... 53
3.1.1 Overview and Summary ............................ 53
3.1.2 Overview of Oxidatively Generated DNA Damage .... 53
3.2 Single Base Damage ..................................... 55
3.2.1 Singlet Oxygen Oxidation of Guanine ............. 55
3.2.2 Hydroxyl Radical Reactions ...................... 58
3.2.2.1 Thymine ................................ 58
3.2.2.2 Guanine ................................ 60
3.2.2.3 Adenine ................................ 62
3.2.3 One-Electron Oxidation of Nucleobases ........... 63
3.2.4 HOC1 Acid-Mediated Halogenation of Pyrimidine
and Purine Bases ................................ 65
3.3 Tandem Base Lesions .................................... 66
3.4 Hydroxyl Radical-Mediated 2-Deoxyribose Oxidation
Reactions .............................................. 67
3.4.1 Hydrogen Abstraction at C4': Formation of
Cytosine Adducts ................................ 67
3.4.2 Hydrogen Atom Abstraction at C5': Formation of
Purine 5',8-Cyclonucleosides .................... 68
3.5 Secondary Oxidation Reactions of Bases ................. 70
3.6 Conclusions and Perspectives ........................... 71
Acknowledgements ............................................ 71
References .................................................. 72
4 Role of Free Radical Reactions in the Formation of DNA
Damage ...................................................... 81
Vladimir Shafirovich and Nicholas E. Geacintov
4.1 Introduction ........................................... 81
4.2 Importance of Free Radical Reactions with DNA .......... 82
4.2.1 Free Radical Mechanisms: General
Considerations .................................. 82
4.2.2 Types of Free Radicals and their Reactions
with Nucleic Acids .............................. 83
4.2.3 Methods for Studying Free Radical Reactions:
Laser Flash Photolysis .......................... 84
4.2.4 Types of Radical Reactions and Kinetics ......... 85
4.2.5 Examples of DNA Radical Reactions ............... 86
4.2.6 Lifetimes of Free Radicals and Environmental
Considerations .................................. 88
4.2.7 Reactions of Free Radicals ...................... 89
4.3 Mechanisms of Product Formation ........................ 91
4.3.1 Reactions of G(-H)'Radicals with Nucleophiles ... 91
4.3.2 Combinations of G(-H)'and Oxyl Radicals ......... 93
4.3.3 Oxidation of 8-oxoG ............................. 97
4.4 Biological Implications ................................ 99
Acknowledgements ........................................... 100
References ................................................. 101
5 DNA Damage Caused by Endogenously Generated Products of
Oxidative Stress ........................................... 105
Charles G. Knutson and Lawrence J. Marnett
5.1 Lipid Peroxidation .................................... 105
5.2 2'-Deoxyribose Peroxidation ........................... 107
5.3 Reactions of MDA and P-Substituted Acroleins with
DNA Bases ............................................. 109
5.4 Stability of M1dG: Hydrolytic Ring-Opening and
Reaction with Nucleophiles ............................ 112
5.5 Propano Adducts ....................................... 114
5.6 Etheno Adducts ........................................ 114
5.7 Mutagenicity of Peroxidation-Derived Adducts .......... 117
5.8 Repair of DNA Damage .................................. 121
5.9 Assessment of DNA Damage .............................. 123
5.10 Conclusions ........................................... 126
Acknowledgements ........................................... 126
References ................................................. 126
6 Polycyclic Aromatic Hydrocarbons: Multiple Metabolic
Pathways and the DNA Lesions Formed ........................ 131
Trevor M. Penning
6.1 Introduction .......................................... 131
6.2 Radical Cation Pathway ................................ 134
6.2.1 Metabolic Activation of PAHs ................... 134
6.2.2 Radical Cation DNA Adducts ..................... 135
6.2.3 Limitations of the Radical Cation Pathway ...... 136
6.3 Diol Epoxides ......................................... 137
6.3.1 Metabolic Activation of PAHs ................... 137
6.3.2 Diol Epoxide-DNA Adducts ....................... 138
6.3.3 Limitations of the Diol Epoxide Pathway ........ 140
6.4 PAH o-Quinones ........................................ 141
6.4.1 Metabolic Activation of PAH trans-
Dihydrodiols by AKRs ........................... 141
6.4.2 PAH o-Quinone-Derived DNA Adducts .............. 142
6.4.2.1 Covalent PAH o-Quinone-DNA Adducts .... 142
6.4.2.2 Oxidative DNA Lesions from PAH
o-Quinones ............................ 144
6.4.3 Limitations of the PAH o-Quinone Pathway ....... 146
6.5 Future Directions ..................................... 147
Acknowledgements ........................................... 148
References ................................................. 148
7 Aromatic Amines and Heterocyclic Aromatic Amines: From
Tobacco Smoke to Food Mutagens ............................. 157
Robert J. Turesky
7.1 Introduction .......................................... 157
7.2 Exposure and Cancer Epidemiology ...................... 157
7.3 Enzymes of Metabolic Activation and Genetic
Polymorphisms ......................................... 159
7.4 Reactivity of N-Hydroxy-AAs and N-Hydroxy-HAAs with
DNA ................................................... 161
7.5 Syntheses of AA-DNA and HAA-DNA Adducts ............... 162
7.6 Biological Effects of AA-DNA and HAA-DNA Adducts ...... 162
7.7 Bacterial Mutagenesis ................................. 164
7.8 Mammalian Mutagenesis ................................. 165
7.9 Mutagenesis in Transgenic Rodents ..................... 166
7.10 Genetic Alterations in Oncogenes and Tumor
Suppressor Genes ...................................... 167
7.11 AA-DNA and HAA-DNA Adduct Formation in Experimental
Animals and Methods of Detection ...................... 168
7.12 AA-DNA and HAA-DNA Adduct Formation in Humans ......... 171
7.13 Future Directions ..................................... 173
Acknowledgements ........................................... 173
References ................................................. 173
8 Cenotoxic Estrogen Pathway: Endogenous and Equine
Estrogen Hormone Replacement Therapy ....................... 185
Judy L. Bolton and Gregory R.J. Thatcher
8.1 Risks of Estrogen Exposure ............................ 185
8.2 Mechanisms of Estrogen Carcinogenesis ................. 187
8.2.1 Hormonal Mechanism ............................. 187
8.2.2 Chemical Mechanism ............................. 188
8.2.2.1 Oxidative DNA Damage .................. 188
8.2.2.2 DNA Adducts ........................... 189
8.2.2.3 Protection against DNA Damage ......... 192
8.3 Estrogen Receptor as a Trojan Horse (Combined
Hormonal/Chemical Mechanism) .......................... 193
8.4 Conclusions and Future Directions ..................... 194
Acknowledgements ...................................... 194
References ................................................. 194
Part Two New Frontiers and Challenges: Understanding
Structure-Function Relationships and Biological
Activity .......................................... 201
9 Interstrand DNA Cross-Linking l,N2-Deoxyguanosine Adducts
Derived from α,β-Unsaturated Aldehydes: Structure-
Function Relationships ..................................... 203
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
9.1 Introduction .......................................... 203
9.2 Interstrand Cross-Linking Chemistry of the γ-OH-PdG
Adduct (9) ............................................ 205
9.3 Interstrand Cross-Linking by the α-CH3-γ-OH-PdG
Adducts Derived from Crotonaldehyde ................... 207
9.4 Interstrand Cross-Linking by 4-HNE .................... 207
9.5 Carbinolamine Cross-Links Maintain Watson-Crick
Base-Pairing .......................................... 209
9.6 Role of DNA Sequence .................................. 210
9.7 Role of Stereochemistry in Modulating Cross-Linking ... 210
9.8 Biological Significance ............................... 212
9.9 Conclusions ........................................... 213
Acknowledgements ........................................... 213
References ................................................. 213
10 Structure-Function Characteristics of Aromatic Amine-DNA
Adducts .................................................... 217
Bongsup Cho
10.1 Introduction .......................................... 217
10.2 Major Conformational Motifs ........................... 219
10.2.1 Fully Complementary DNA Duplexes ............... 219
10.2.2 Other Sequence Contexts ........................ 220
10.3 Conformational Heterogeneity .......................... 221
10.3.1 Sequence Effects on the S/B Conformational
Heterogeneity .................................. 222
10.3.2 Conformational Dynamics of the S/B
Heterogeneity .................................. 224
10.3.3 Base Sequence Context and Mutagenesis .......... 224
10.3.4 Dependence of Nucleotide Excision Repair by
E. coli UvrABC Proteins on Adduct
Conformation ................................... 225
10.3.5 Conformational Heterogeneity in Translesion
Synthesis ...................................... 227
10.3.6 Sequence Effects on the Conformational
Stability of SMIs .............................. 230
10.4 Structures of DNA Lesion-DNA Polymerase Complexes ..... 231
10.5 Conclusions ........................................... 232
Acknowledgements ........................................... 233
References ................................................. 233
11 Mechanisms of Base Excision Repair and Nucleotide
Excision Repair ............................................ 239
Orlando D. Schärer and Arthur J. Campbell
11.1 General Features of Base Excision and Nucleotide
Excision Repair ....................................... 239
11.2 BER ................................................... 241
11.2.1 BER Overview-Short-Patch and Long-Patch BER .... 241
11.2.2 Lesion Recognition by DNA Glycosylases ......... 242
11.2.3 Passing the Baton-Abasic Site Removal and
Repair ......................................... 247
11.3 NER ................................................... 248
11.3.1 Subpathways of NER: Global Genome and
Transcription-Coupled NER ...................... 248
11.3.2 Damage Recognition in GG-NER ................... 248
11.3.3 Damage Verification and Lesion Demarcation in
NER ............................................ 251
11.3.4 Dual-Incision and Repair Synthesis in NER ...... 252
11.3.5 Damage Recognition in TC-NER ................... 252
11.4 Conclusions ........................................... 254
References ................................................. 254
12 Recognition and Removal of Bulky DNA Lesions by the
Nucleotide Excision Repair System .......................... 261
Yuqin Cai, Konstantin Kropachev, Marina Kolbanovskiy,
Alexander Kolbanovskiy, Suse Broyde, Dinshaw J. Patel,
and Nicholas E. Geacintov
12.1 Introduction .......................................... 261
12.2 Overview of Mammalian NER ............................. 261
12.3 Prokaryotic NER ....................................... 263
12.4 Recognition of Bulky Lesions by Mammalian NER
Factors ............................................... 263
12.5 Bipartite Model of Mammalian NER and the
Multipartite Model of Lesion Recognition .............. 264
12.6 DNA Lesions Derived from the Reactions of PAH Diol
Epoxides with DNA are Excellent Substrates for
Probing the Mechanisms of NER ......................... 265
12.7 Multidisciplinary Approach Towards Investigating
Structure-Function Relationships in the NER of Bulky
PAH-DNA Adducts ....................................... 268
12.8 Dependence of DNA Adduct Conformations and NER on
PAH Topology and Stereochemistry ...................... 269
12.8.1 Guanine B[α]P Adducts (Figure 12.3a): Minor
Groove and Base-Displaced/Intercalative
Conformations .................................. 270
12.8.2 Bay Region B[α]P-N6-Adenine Adducts (Figure
12.3b): Distorting Intercalative Insertions
from the Major Groove .......................... 271
12.8.3 Fjord Region PAH N6-Adenine Adducts (Figure
12.3c and d): Minimally Distorting
Intercalation from the Major Groove ............ 272
12.8.4 Dependence of NER Efficiencies on the
Conformations of the Bay Region B[α]P-N2-dG
Adducts ........................................ 272
12.8.5 NER Efficiencies: Bay and Fjord Region PAH
Diol Epoxide-N6-dA Adducts ..................... 278
12.8.6 Why the trans-anti-B[c]Ph-N6-dA and Related
Fjord Region N6-dA Adducts do not Destabilize
DNA and are Resistant to NER ................... 280
12.9 Dependence of NER of the 10S (+)-trans-anti-
B[α]P-N2-dG Adduct on Base Sequence Context ........... 280
12.9.1 Structural Characteristics of the Identical
10S (+)-trans-anti-B[α]P-N2-dG Adduct in
Different Sequence Contexts .................... 281
12.9.1.1 CG*C and TG*T Sequences ............... 282
12.9.1.2 G6*G7, G6G7*, and 16G7* Sequences ..... 282
12.9.2 Hierarchies of Mammalian NER Recognition
Signals ........................................ 286
12.10 Conclusions .......................................... 287
Acknowledgements ........................................... 289
References ................................................. 289
13 Impact of Chemical Adducts on Translesion Synthesis in
Replicative and Bypass DNA Polymerases: From Structure to
Function ................................................... 299
Robert L. Eoff, Martin Egli, and F. Peter Guengerich
13.1 Introduction .......................................... 299
13.2 Bypass of Abasic Sites ................................ 302
13.3 Lesions Generated by Oxidative Damage to DNA .......... 305
13.4 Exocyclic DNA Adduct Bypass ........................... 308
13.5 Alkylated DNA ......................................... 310
13.6 Polycyclic Aromatic Hydrocarbons and the Effect of
Adduct Size upon Polymerase Catalysis ................. 313
13.7 Cyclobutane Pyrimidine Dimers and UV Photoproducts .... 316
13.8 Inter-and Intrastrand DNA Cross-Links ................. 316
13.9 Conclusions ........................................... 318
References ................................................. 319
14 Elucidating Structure-Function Relationships in Bulky DNA
Lesions: From Solution Structures to Polymerases ........... 331
Suse Broyde, Lihua Wang, Dinshaw J. Patel, and Nicholas
E. Geacintov
14.1 Introduction .......................................... 331
14.2 Benzo[α]pyrene-Derived DNA Lesions as a Useful
Model ................................................. 331
14.3 Computational Elucidation of the Structural
Properties of B[α]P-Derived DNA Lesions in Solution ... 333
14.4 DNA Polymerase Structure-Function Relationships
Elucidated with B[α]P-Derived Lesions ................. 335
14.5 Mechanism of the Nucleotidyl Transfer Reaction ........ 343
14.6 Conclusions and Future Perspectives ................... 345
Acknowledgements ........................................... 345
References ................................................. 346
15 Translesion Synthesis and Mutagenic Pathways in
Escherichia coli Cells ..................................... 353
Sushil Chandani and Edward L. Loechler
15.1 Introduction .......................................... 353
15.2 Mutagenesis in E. coli has Illuminated Our
Understanding of Mutagenesis in General ............... 354
15.3 Why Does E. coli have Three Translesion Synthesis
DNA Polymerases? ...................................... 356
15.4 Overview of the Steps Leading to Translesion
Synthesis ............................................. 358
15.5 Case Studies: AAF-C8-dG and N2-dG Adducts, Such as
+BP ................................................... 360
15.6 Structure-Function Analysis of Y-Family Pols IV and
V of E. coli .......................................... 362
15.6.1 Structural Basis for a Large versus Small
Chimney Opening ................................ 366
15.6.2 Roof-Amino Acids and Roof-Neighbor-Ammo
Acids .......................................... 368
15.6.3 Interconnected Architecture of the Chimney
and Roof Regions ............................... 368
15.6.4 dCTP Insertion by Pol IV ....................... 369
15.6.5 How Does UmuC(V) Insert dATP? .................. 370
15.6.6 A Cautionary Note about Dpo4 ................... 371
15.6.7 Why is Pol IV Efficient at Extension with
-BP, but Inefficient with +BP? ................. 372
15.7 Y-Family DNA Polymerase Mechanistic Steps ............. 373
15.8 Structure of B-Family Pol II of E. coli ............... 373
References ................................................. 374
16 Insight into the Molecular Mechanism of Translesion DNA
Synthesis in Human Cells using Probes with Chemically
Defined DNA Lesions ........................................ 381
Zvi Livneh
16.1 Introduction .......................................... 381
16.2 Overview of TLS ....................................... 382
16.3 Plasmid Model Systems with Defined Lesions for
Studying TLS .......................................... 384
16.4 Gap-Lesion Plasmid Assay for Mammalian TLS ............ 384
16.5 Some Lesions are Bypassed Most Effectively and Most
Accurately by Specific Cognate TLS DNA Polymerases .... 387
16.6 Pivotal Role for Pol ζ in TLS Across a Wide Variety
of DNA Lesions ........................................ 388
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 ................................................. 388
16.8 Evidence that TLS Occurs by Two-Polymerase
Mechanisms, in Combinations that Determine the
Accuracy of the Process ............................... 391
16.9 Conclusions ........................................... 393
Acknowledgements ........................................... 393
References ................................................. 394
17 DNA Damage and Transcription Elongation: Consequences and
RNA Integrity .............................................. 399
Kristian Dreij, John A. Burns, Alexandra Dimitri, Lana
Nirenstein, Taissia Noujnykh, and David A. Scicchitano
17.1 Introduction .......................................... 399
17.2 DNA Repair ............................................ 400
17.3 Transcription Elongation and DNA Damage ............... 402
17.4 RNA Polymerases: A Brief Overview ..................... 402
17.5 RNA Polymerase Elongation Past DNA Damage ............. 407
17.5.1 Abasic Sites, Single-Strand Nicks, and Gaps .... 407
17.5.2 Oxidative DNA Damage ........................... 408
17.5.3 Alkylated Bases in DNA ......................... 412
17.5.4 Intrastrand and Interstrand DNA Cross-links .... 414
17.5.5 "Bulky" DNA Adducts ............................ 416
17.6 Conclusions ........................................... 421
Acknowledgements ........................................... 428
References ................................................. 429
Index ......................................................... 439
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