Abstract

Many antitumor and antiviral agents exert their therapeutic and toxic effects by creating structural or conformational changes in DNA. Mutagens and chemical carcinogens appear to be involved in similar interactions. The common event to these phenomena is the interaction of a small molecule with DNA. The experiments described in this proposal are designed to identify specific sites in DNA which bind antitumor drugs and carcinogens. We propose to apply this information to the use of drugs as molecular probes of chromatin structure. Recombinant DNA techniques will be employed to explore the relationship between drug-induced damage to DNA and mutagenesis. Finally, we propose an extension of our ongoing work on the mechanism of action of bleomycin. The long term goals of this research are aimed at elucidating the molecular basis of drug- and carcinogen-interactions with DNA. Studies of this type should enhance greatly our understanding of carcinostatic and carcinogenic mechanisms. In addition, structure-activcity relationships will be established that can ultimately be applied in the rational design of drugs that modulate the biological effects of DNA.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA017395-12
Application #
3164694
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1977-01-01
Project End
1988-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
12
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

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

  Publications

Li, Haoquan; Endutkin, Anton V; Bergonzo, Christina et al. (2017) DNA Deformation-Coupled Recognition of 8-Oxoguanine: Conformational Kinetic Gating in Human DNA Glycosylase. J Am Chem Soc 139:2682-2692
Li, Haoquan; Endutkin, Anton V; Bergonzo, Christina et al. (2016) A dynamic checkpoint in oxidative lesion discrimination by formamidopyrimidine-DNA glycosylase. Nucleic Acids Res 44:683-94
Gao, Shujuan; Honey, Sangeet; Futcher, Bruce et al. (2016) The non-homologous end-joining pathway of S. cerevisiae works effectively in G1-phase cells, and religates cognate ends correctly and non-randomly. DNA Repair (Amst) 42:1-10
Kuznetsov, Nikita A; Bergonzo, Christina; Campbell, Arthur J et al. (2015) Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition. Nucleic Acids Res 43:272-81
Lukina, Maria V; Popov, Alexander V; Koval, Vladimir V et al. (2013) DNA damage processing by human 8-oxoguanine-DNA glycosylase mutants with the occluded active site. J Biol Chem 288:28936-47
Kuznetsov, Nikita A; Koval, Vladimir V; Zharkov, Dmitry O et al. (2012) Conformational dynamics of the interaction of Escherichia coli endonuclease VIII with DNA substrates. DNA Repair (Amst) 11:884-91
Bergonzo, Christina; Campbell, Arthur J; de los Santos, Carlos et al. (2011) Energetic preference of 8-oxoG eversion pathways in a DNA glycosylase. J Am Chem Soc 133:14504-6
Kirpota, Oleg O; Endutkin, Anton V; Ponomarenko, Michail P et al. (2011) Thermodynamic and kinetic basis for recognition and repair of 8-oxoguanine in DNA by human 8-oxoguanine-DNA glycosylase. Nucleic Acids Res 39:4836-50
Mechetin, Grigory V; Zharkov, Dmitry O (2011) Mechanism of translocation of uracil-DNA glycosylase from Escherichia coli between distributed lesions. Biochem Biophys Res Commun 414:425-30
Zharkov, Dmitry O; Mechetin, Grigory V; Nevinsky, Georgy A (2010) Uracil-DNA glycosylase: Structural, thermodynamic and kinetic aspects of lesion search and recognition. Mutat Res 685:11-20

Showing the most recent 10 out of 98 publications