The Chemical Biology of DNA Damage

Bacterial Mutagenesis Mammalian Mutagenesis Mutagenesis in Transgenic Rodents Genetic Alterations in Oncogenes and Tumor Suppressor Genes AA-DNA and HAA-DNA Adduct Formation in Humans Future Directions GENOTOXIC ESTROGEN PATHWAY: ENDOGENOUS AND EQUINE ESTROGEN HORMONE REPLACEMENT THEORY Risks of Estrogen Exposure Mechanisms of Estrogen Carcinogenesis Estrogen Receptor as a Trojan Horse (Combined Hormonal/Chemical Mechanism) Conclusions and Future Directions PART II: New Frontiers and Challenges: Understanding Structure-Function Relationships and Biological Activity INTERSTRAND DNA CROSS-LINKING 1,N2-DEOXYGUANOSINE ADDUCTS DERIVED FROM ALPHA, BETA-UNSATURATED ALDEHYDES: STRUCTURE-FUNCTION RELATIONSHIPS Introduction Interstrand Cross-Linking Chemistry of the Gamma-OH-PdG Adduct (9) Interstrand Cross-Linking by the Alpha-CH3-Yamma-OH-PG Adducts Derived from Crotonaldehyde Interstrand Cross-Linking by 4-HNE Carbinolamine Cross-Links Maintain Watson-Crick Base-Pairing Role of DNA Sequence Role of Stereochemistry in Modulating Cross-Linking Biological Significance Conclusions STRUCTURE-FUNCTION CHARACTERISTICS OF AROMATIC AMINE-DNA ADDUCTS Introduction Major Conformational Motifs Conformational Heterogeneity Structures of DNA Lesion-DNA Polymerase Complexes Conclusions MECHANISMS OF BASE EXCISION REPAIR AND NUCLEOTIDE EXCISION REPAIR General Features of Base Excision and Nucleotide Excision Repair BER NER Conclusions RECOGNITION AND REMOVAL UF BULKY DNA LESIONS BY THE NUCLEOTIDE EXCISION REPAIR SYSTEM Introduction Overview of Mammalian NER Prokaryotic NER Recognition of Bulky Lesions by Mammalian NER Factors Bipartite Model of Mammalian NER and the Multipartite Model of Lesion Recognition DNA Lesions Derived from the Reactions of PAH Diol Epoxides with DNA are Excellent Substrates for Probing the Mechanisms of NER Multidisciplinary Approach Towards Investigating Structure-Function Relationships in the NER of Bulky PAH-DNA Adducts Dependence of DNA Adduct Conformations and NER on PAH Topology and Stereochemistry Dependence of NER of the 10S (+)-trans-anti-B[a]P-N2-dG Adduct on Base Sequence Context Conclusions IMPACT OF CHEMICAL ADDUCTS ON TRANSLESION SYNTHESIS IN REPLICATIVE AND BYPASS DNA POLYMERASES: FROM STRUCTURE TO FUNCTION Introduction Bypass of Abasic Sites Lesions Generated by Oxidative Damage to DNA Exocyclic DNA Adduct Bypass Alkylated DNA Polycyclic Aromatic Hydrocarbons and the Effect of Adduct Size upon Polymerase Catalysis Cyclobutane Pyrimidine Dimers and UV Photoproducts Inter- and Intrastrand DNA Cross-Links Conclusions ELUCIDATING STRUCTURE-FUNCTION RELATIONSHIPS IN BULKY DNA LESIONS: FROM SOLUTION STRUCTURES TO POLYMERASES Introduction Benzo[a]pyrene-Derived DNA Lesions as a Useful Model Computational Elucidation of the Structural Properties of B[a]P-Derived DNA Lesions in Solution DNA Polymerase Structure-Function Relationships Elucidated with B[a]P-Derived Lesions Mechanism of the Nucleotidyl Transfer Reaction Conclusions and Future Perspectives TRANSLESION SYNTHESIS AND MUTAGENIC PATHWAYS IN ESCHERICHIA COLI CELLS Introduction Mutagenesis in E. coli has Illuminated Our Understanding of Mutagenesis in General Why Does E. coli have Three Translesion Synthesis DNA Polymerases? Overview of the Steps Leading to Translesion Synthesis Case Studies: AAF-C8-dG and N2-dG Adducts, Such as +BP Structure-Function Analysis of Y-Family Pols IV and V of E. coli Y-Family DNA Polymerase Mechanistic Steps Structure of B-Family Pol II of E. coli INSIGHT INTO THE MOLECULAR MECHANISM OF TRANSLESION DNA SYNTHESIS IN HUMAN CELLS USING PROBES WITH CHEMICALLY DEFINED DNA LESIONS Introduction Overview of TLS Plasmid Model Systems with Defined Lesions for Studying TLS Gap-Lesion Plasmid Assay for Mammalian TLS Some Lesions are Bypassed Most Effectively and Most Accurately by Specific Cognate TLS DNA Polymerases Pivotal Role for Pol Zeta in TLS Across a Wide Variety of DNA Lesions 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 Evidence that TLS Occurs by Two-Polymerase Mechanisms, in Combinations that Determine the Accuracy of the Process Conclusions DNA DAMAGE AND TRANSCRIPTION ELONGATION: CONSEQUENCES AND RNA INTEGRITY Introduction DNA Repair Transcription Elongation and DNA Damage RNA Polymerases: A Brief Overview RNA Polymerase Elongation Past DNA Damage Conclusions