(Applicant's Description) The central theme of this Program Project will remain focused on the relationship between molecular structure, thermodynamics, and biological function. By developing novel biological systems that reflect the mutagenic specificity of a single DNA adduct and by using NMR spectroscopy and thermodynamic analysis to establish three-dimensional coordinates and physical properties of duplex DNA containing these adducts, fundamental relationships between structure, energetics, and biological activity can be established. This information will enable us to elucidate and explain mechanisms of mutagenesis and DNA repair at the molecular level. In turn, biological observation raise structural and thermodynamic questions that bring the process of inquiry full circle. Important correlations between structure, energetics, and biological activity have begun to emerge from this research. Insights have been gained into structural and conformational changes which lead to miscoding and/or misalignment of templates during DNA replication. Establishing the three dimensional structure and physical properties of chemically-modified DNA has allowed us to propose mechanisms by which DNA repair enzymes recognize and excise lesions from damaged DNA. Accurate structural and mechanistic information is central to understanding DNA replication and mutagenesis. Mutagenesis produced by endogenous DNA damage, including DNA adducts and oxidized bases is related microscopically to molecular structure and macroscopically to thermodynamics and kinetics, thereby providing a mechanistic rationale for this interdisciplinary research program. The long term goals of this Program include (I) developing new synthetic methods that allow defined lesions to be introduced site-specifically into DNA, (ii) characterizing thermodynamic and extra-thermodynamic impacts of mutagenic lesions on conformational preferences, temperature-dependent transitions, and melting cooperativities of DNA duplexes containing lesions of interest, (iii) determining site-specifically mutational spectra of DNA adducts in human cels and elucidating molecular mechanisms involved in mutagenesis and DNA repair, (iv) relating biological and physical properties of damaged DNA to their three dimensional structure, as determined by 2D NMR and computer-assisted molecular modeling techniques.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA047995-09
Application #
2839699
Study Section
Subcommittee G - Education (NCI)
Program Officer
Okano, Paul
Project Start
1990-04-01
Project End
2004-01-31
Budget Start
1999-06-15
Budget End
2000-01-31
Support Year
9
Fiscal Year
1999
Total Cost
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

Showing the most recent 10 out of 123 publications