The broad and long term goals of this research is to determine on a molecular level the etiology of cancer initiation by DNA damage, produced by environmental and endogenous chemicals to which the human population is widely exposed. The overall hypotheses are: (1) The specific formation of damaged DNA is critical in determining if it is repaired or not;(2) if repair fails, the DNA conformation within a replicative polymerase determines whether blockage, normal or mutagenic bypass occurs;(3) if normal replication is impeded, then the altered DNA will encounter one or more bypass polymerases, and the specific conformation of the altered DNA will determine whether a mutation which may initiate cancer occurs. The PI will test these hypotheses by determining structural, dynamic and thermodynamic properties for two groups of lesions: (1) a series derived from carcinogenic aromatic amines/amide presenting tobacco smoke, automobile exhaust and cooked foods that are capable of Watson-Crick pairing and stacking, and (2) a severely distorting group incapable of Watson-Crick pairing, with impaired stacking;these include a lesion derived from a prominent hormone replacement drug, and one produced by endogenous and exogenous reactive oxygen species.
Specific aim 1 will determine detailed structural and thermodynamic properties of the lesions in duplex DNA as a function of adduct structure and thermodynamic factors that cause the adducts to impede replicative polymerases, and to delineate factors which could permit mutagenic or normal bypass of the lesions with lowered fidelity in Y-family bypass polymerases. Relevance to public health: this work will define precisely on a molecular level, the specific structural and energetic characteristics of DNA-containing lesions derived from carcinogenic environmental substances, and thus provided the molecular hallmarks that distinguish very harmful chemicals from benign ones. These studies will facilitate advances in biomonitoring of carcinogen - damaged DNA, since the structural and thermodynamic properties of the DNA lesions would provide a method for distinguishing highly genotoxic lesions from more benign ones.
|Mu, Hong; Geacintov, Nicholas E; Broyde, Suse et al. (2018) Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair. DNA Repair (Amst) :|
|Chakraborty, Sagnik; Steinbach, Peter J; Paul, Debamita et al. (2018) Enhanced spontaneous DNA twisting/bending fluctuations unveiled by fluorescence lifetime distributions promote mismatch recognition by the Rad4 nucleotide excision repair complex. Nucleic Acids Res 46:1240-1255|
|Ji, Shaofei; Fu, Iwen; Naldiga, Spandana et al. (2018) 5-Formylcytosine mediated DNA-protein cross-links block DNA replication and induce mutations in human cells. Nucleic Acids Res 46:6455-6469|
|Cai, Yuqin; Fu, Iwen; Geacintov, Nicholas E et al. (2018) Synergistic effects of H3 and H4 nucleosome tails on structure and dynamics of a lesion-containing DNA: Binding of a displaced lesion partner base to the H3 tail for GG-NER recognition. DNA Repair (Amst) 65:73-78|
|Fu, Iwen; Cai, Yuqin; Geacintov, Nicholas E et al. (2017) Nucleosome Histone Tail Conformation and Dynamics: Impacts of Lysine Acetylation and a Nearby Minor Groove Benzo[a]pyrene-Derived Lesion. Biochemistry 56:1963-1973|
|Geacintov, Nicholas E; Broyde, Suse (2017) Repair-Resistant DNA Lesions. Chem Res Toxicol 30:1517-1548|
|Mu, Hong; Geacintov, Nicholas E; Min, Jung-Hyun et al. (2017) Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway. Chem Res Toxicol 30:1344-1354|
|Fu, Iwen; Cai, Yuqin; Zhang, Yingkai et al. (2016) Entrapment of a Histone Tail by a DNA Lesion in a Nucleosome Suggests the Lesion Impacts Epigenetic Marking: A Molecular Dynamics Study. Biochemistry 55:239-42|
|Wickramaratne, Susith; Ji, Shaofei; Mukherjee, Shivam et al. (2016) Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases. J Biol Chem 291:23589-23603|
|Cai, Yuqin; Kropachev, Konstantin; Terzidis, Michael A et al. (2015) Differences in the Access of Lesions to the Nucleotide Excision Repair Machinery in Nucleosomes. Biochemistry 54:4181-5|
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