Oxidative DNA damage, and exocyclic DNA adducts are involved in the initiation of mutations that lead to human cancer. This Program Project focuses on characterizing the mechanisms by which damaged DNA is recognized, replicated and repaired. The program theme involves elucidation of relations among molecular structure, energetics and biological function, incorporating the expertise of chemists, biophysicists, structural, cell and molecular biologists in this endeavor. As a result of these efforts, novel biological systems have been developed that reflect the mutagenic specificity of a single DNA adduct. X-ray crystallography and NMR spectroscopy are used to establish structures of key enzymes complexed to oxidatively damaged DNA. Significant correlations between structure, energetics, and biological activity are expected to emerge from this interdisciplinary research. We will characterize conformational changes and energetic perturbations induced by DNA damage, and assess how these perturbations modulate damage recognition, DNA repair, and miscoding events. We will establish three-dimensional structures and characterize the energetics of DNA glycosylases and DNA polymerases bound to their cognate DNA substrates. The molecular and energetic origins of the functions of these key enzymes, as defined by structural studies and thermodynamic measurements, will be explored by site-directed mutagenesis techniques, thereby illuminating molecular mechanisms of mutagenesis and carcinogenesis. The long-term goals of the Program include: (i) elucidating mechanisms of translesion synthesis, mutagenesis, and base excision repair in human cells; (ii) relating the molecular structure of DNA polymerases and glycosylases to their biological functions of replication and repair of damaged DNA; and (iii) characterizing the structural and energetic consequences of DNA lesions, relating lesion-induced alterations to biological function as manifest in DNA recognition, repair, and replication by DNA glycosylases and polymerases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047995-18
Application #
7390698
Study Section
Subcommittee G - Education (NCI)
Program Officer
Okano, Paul
Project Start
1990-04-01
Project End
2011-12-30
Budget Start
2008-03-01
Budget End
2011-12-30
Support Year
18
Fiscal Year
2008
Total Cost
$1,265,508
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Minetti, Conceição A S A; Remeta, David P; Iden, Charles R et al. (2015) Impact of thymine glycol damage on DNA duplex energetics: Correlations with lesion-induced biochemical and structural consequences. Biopolymers 103:491-508
Völker, Jens; Plum, G Eric; Gindikin, Vera et al. (2014) Impact of bulge loop size on DNA triplet repeat domains: Implications for DNA repair and expansion. Biopolymers 101:1-12
Li, Mengxia; Völker, Jens; Breslauer, Kenneth J et al. (2014) APE1 incision activity at abasic sites in tandem repeat sequences. J Mol Biol 426:2183-98
Braunlin, William; Völker, Jens; Plum, G Eric et al. (2013) DNA meter: Energy tunable, quantitative hybridization assay. Biopolymers 99:408-17
Völker, Jens; Gindikin, Vera; Klump, Horst H et al. (2012) Energy landscapes of dynamic ensembles of rolling triplet repeat bulge loops: implications for DNA expansion associated with disease states. J Am Chem Soc 134:6033-44
Lukin, Mark; Minetti, Conceicao A S A; Remeta, David P et al. (2011) Novel post-synthetic generation, isomeric resolution, and characterization of Fapy-dG within oligodeoxynucleotides: differential anomeric impacts on DNA duplex properties. Nucleic Acids Res 39:5776-89
Völker, Jens; Plum, G Eric; Klump, Horst H et al. (2010) Energetic coupling between clustered lesions modulated by intervening triplet repeat bulge loops: allosteric implications for DNA repair and triplet repeat expansion. Biopolymers 93:355-69
Zaliznyak, Tanya; Lukin, Mark; El-khateeb, Mahmoud et al. (2010) NMR structure of duplex DNA containing the alpha-OH-PdG.dA base pair: a mutagenic intermediate of acrolein. Biopolymers 93:391-401
Minetti, Conceição A S A; Remeta, David P; Johnson, Francis et al. (2010) Impact of alpha-hydroxy-propanodeoxyguanine adducts on DNA duplex energetics: opposite base modulation and implications for mutagenicity and genotoxicity. Biopolymers 93:370-82
Minetti, Conceicao A S A; Remeta, David P; Dickstein, Rian et al. (2010) Energetic signatures of single base bulges: thermodynamic consequences and biological implications. Nucleic Acids Res 38:97-116

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