DNA damage is an Initiating step in cancer etiology. This renewal focuses upon understanding the chemistry and biology of various types of DNA damage, which are directly or indirectly related to various sources of cellular oxidative stress and inflammation, and significant with respect to cancer etiology. An ancillary theme is that once formed, these adducts often undergo further chemistry, which may be reversible, e.g., in the case of malondialdehyde (MDA), 5,6-dihydroxy-dihydro-2'-thymlne or Tg, or Irreversible, in the case of aflatoxin B{1} (AFB{1}). Indeed, some of the secondary lesions;e.g., DNA cross-links or N7-dG FAPY lesions, are more deleterious than are the initial lesions. Their chemistry and biological processing depend upon whether the DNA exists as a duplex or is single-stranded, and depends upon the sequence and identity of the complementary nucleotide. If the aims of this application are successful, structure-activity relationships delineating the complex chemistry of these lesions, and the resulting structural alterations to DNA, and their interactions with DNA processing enzymes will be obtained, which will translate into an understanding as to how their respective chemistry modulates their biological processing;our work may also facilitate the identification of potential new targets for chemotherapeutic intervention in human disease.

Public Health Relevance

The goal is to understand mechanisms by which exposures to malondialdehyde, aflatoxin B{1} and specific oxidative damages to thymine and guanine contribute to the etiology of cancer. Each is directly or indirectly related to cellular oxidative stress and inflammation. Malondialdehyde, aflatoxin B{1} and thymine glycol DNA adducts also undergo transformations once formed, e.g., unmasking new chemical functionality that may differentially modulate repair and replication, or facilitate secondary chemistry such as formation of interstrand cross-links. Understanding the structure-activity relationships delineating the chemistry of these lesions, their structural alterations to DNA, and interactions with DNA processing enzymes will translate into an understanding as to how their chemistry modulates biological processing: our work may also facilitate the identification of targets for chemotherapeutic intervention in human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055678-21
Application #
8534710
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
1992-02-15
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
21
Fiscal Year
2013
Total Cost
$269,602
Indirect Cost
$85,469
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lin, Ying-Chih; Owen, Nichole; Minko, Irina G et al. (2016) DNA polymerase ζ limits chromosomal damage and promotes cell survival following aflatoxin exposure. Proc Natl Acad Sci U S A 113:13774-13779
Patra, Amritraj; Politica, Dustin A; Chatterjee, Arindom et al. (2016) Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase η. Chembiochem 17:2033-2037
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Stavros, Kallie M; Hawkins, Edward K; Rizzo, Carmelo J et al. (2015) Base-Displaced Intercalated Conformation of the 2-Amino-3-methylimidazo[4,5-f]quinoline N(2)-dG DNA Adduct Positioned at the Nonreiterated G(1) in the NarI Restriction Site. Chem Res Toxicol 28:1455-68
Szulik, Marta W; Voehler, Markus; Stone, Michael P (2014) NMR analysis of base-pair opening kinetics in DNA. Curr Protoc Nucleic Acid Chem 59:7.20.1-18
Patra, Amritraj; Nagy, Leslie D; Zhang, Qianqian et al. (2014) Kinetics, structure, and mechanism of 8-Oxo-7,8-dihydro-2'-deoxyguanosine bypass by human DNA polymerase η. J Biol Chem 289:16867-82

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