The structure and energetics of damaged DNA alter normal cellular functions and induce DNA repair. The presence of oxidative DNA damage and exocyclic DNA lesions leads to miscoding during DNA replication, a process associated with mutagenesis, cancer and other age-related diseases. The conformation of mutagenic intermediates, together with the properties of DNA polymerases, determines the ultimate outcome of this process. The goal of this project is to perform the structural characterization of lesion-containing DNA and, in so doing, advance our knowledge of damage recognition by DNA giycosylases and of translesion synthesis catalyzed by DNA polymerases.
The specific aims of Project 4 involve (a) the use of multidimensional solution-state NMR spectroscopy coupled with restrained molecular dynamics simulations to establish three-dimensional structures of DNA duplexes containing exocyclic and oxidative DNA lesions; (b) the application of specifically labeled [15N] and [13C] exocyclic adducts to explore dynamic processes related to translesion synthesis and to identify functional groups in the lesion involved in the recognition of oxidative damage; (c) the performance of unrestrained molecular dynamics simulations to elucidate mechanisms of lesion recognition by DNA glycosylases and the energetics of damaged-base eversion from DNA duplexes. Our structural studies are designed to generate information at the molecular level with respect to structural determinants in the recognition of damaged DNA, and to inform the analysis of translesion synthesis events, complementing mutagenesis, crystallographic, and thermodynamic studies conducted in this Program. These interactions are expected to provide new insights on molecular mechanisms associated with lesion formation, DNA repair, and mutagenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047995-18
Application #
7576093
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
18
Fiscal Year
2008
Total Cost
$210,675
Indirect Cost
Name
State University New York Stony Brook
Department
Type
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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