The overall goal of this research program is to elucidate, at the molecular level, the biological processing and consequences of free radical-induced DNA lesions produced by normal oxidative metabolism, the radiolysis of water, and a variety of chemical pollutants. These lesions constitute the preponderant class of cellular DNA damages and are removed by base excision repair. An unrepaired DNA lesion may block replication casing cellular cytotoxicity or may direct incorporation of an incorrect base leading to mutagenesis. Thus, the biological fate of the damaged cell depends upon the efficiency of repair and the interaction between the lesion and the replication apparatus. To examine the molecular processing of free radical-induced DNA damage, this laboratory has used the strategy of incorporating chemically synthesized model lesions into DNA substrates to study base excision repair in vivo, into templates for DNA synthesis in vitro to predict cytotoxicity and mutagenicity, and into biologically active transfecting DNA to confirm the in vitro predictions. The proposed studies specifically address the structural features of DNA lesions that putatively influence repair efficiency and mutagenic specificity, thus biological consequence and include cloning the genes for new and known enzymes involved in base excision repair processing. This work is driven by the hypothesis that unrepaired DNA lesions play a major role in carcinogenesis. This link is particularly relevant because free radical- induced damages are formed to such a large extent on a daily basis by metabolic oxygen that base excision repair enzymes are likely to be tumor suppressors. Accordingly, elucidating the enzymatic and biological processing of free radical-induced lesions should increase our understanding of the etiology of breast and other forms of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37CA033657-15
Application #
2088591
Study Section
Radiation Study Section (RAD)
Project Start
1982-04-01
Project End
1999-11-30
Budget Start
1995-02-21
Budget End
1995-11-30
Support Year
15
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Wallace, Susan S (2013) DNA glycosylases search for and remove oxidized DNA bases. Environ Mol Mutagen 54:691-704
Faucher, Frédérick; Wallace, Susan S; Doublié, Sylvie (2009) Structural basis for the lack of opposite base specificity of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase. DNA Repair (Amst) 8:1283-9
Yang, Ning; Chaudhry, M Ahmad; Wallace, Susan S (2006) Base excision repair by hNTH1 and hOGG1: a two edged sword in the processing of DNA damage in gamma-irradiated human cells. DNA Repair (Amst) 5:43-51
Bandaru, Viswanath; Blaisdell, Jeffrey O; Wallace, Susan S (2006) Oxidative DNA glycosylases: recipes from cloning to characterization. Methods Enzymol 408:15-33
Watanabe, Takashi; Blaisdell, Jeffrey O; Wallace, Susan S et al. (2005) Engineering functional changes in Escherichia coli endonuclease III based on phylogenetic and structural analyses. J Biol Chem 280:34378-84
Bandaru, Viswanath; Cooper, Wendy; Wallace, Susan S et al. (2004) Overproduction, crystallization and preliminary crystallographic analysis of a novel human DNA-repair enzyme that recognizes oxidative DNA damage. Acta Crystallogr D Biol Crystallogr 60:1142-4
Yang, Ning; Galick, Heather; Wallace, Susan S (2004) Attempted base excision repair of ionizing radiation damage in human lymphoblastoid cells produces lethal and mutagenic double strand breaks. DNA Repair (Amst) 3:1323-34
Doublie, Sylvie; Bandaru, Viswanath; Bond, Jeffrey P et al. (2004) The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity. Proc Natl Acad Sci U S A 101:10284-9
Kathe, Scott D; Shen, Guang-Ping; Wallace, Susan S (2004) Single-stranded breaks in DNA but not oxidative DNA base damages block transcriptional elongation by RNA polymerase II in HeLa cell nuclear extracts. J Biol Chem 279:18511-20
Wallace, Susan S; Bandaru, Viswanath; Kathe, Scott D et al. (2003) The enigma of endonuclease VIII. DNA Repair (Amst) 2:441-53

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