Abstract

The analytical chemistry and organic syntheses developed in this Project provide an essential underpinning for this Program. Experiments are designed to identify chemically-modified nucleotides formed by the reac- tions of certain chemotherapeutic agents and genotoxic compounds with native DNA. The mechanism and sequence specificity of cross-link formation will be investigated using sequence-defined duplex oligodeoxynucleotides. Exocyclic adducts, alkylation products, and cross-linked deoxynucleotides will be identified using advanced detection techniques of FAB mass spectro- metry, thermospray LC/MS, nuclear magnetic resonance, and high performance and liquid chromatography. In additional experiments, organic syntheses leading to single strand oligodeoxynucleotides of defined base sequence containing a single chemi- cally-modified site are proposed. Known exocyclic products of the reaction of DNA with BCNU, acrolein, and vinyl chloride, will be synthesized, converted to their phosphoramidites and incorporated into synthetic oligodeoxynucleotides using solid state techniques. New protecting groups for protection of the nucleoside phosphoramidites used in solid state DNA synthesis will be developed. This will permit the inclusion of the alkali- sensitive adducts into synthetic oligomers.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA047995-07
Application #
6237006
Study Section
Project Start
1997-04-23
Project End
1998-01-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

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