Recent studies have demonstrated that genetic polymorphisms occur within the genes that comprise the major DNA repair pathways. Mutations within many of these genes can lead to increased toxicity and mutagenicity. Within the base excision repair pathway, one of the primary DNA lesions that is repaired is an oxidatively damaged guanine, 8-oxoG. The accumulation of this lesion has been correlated with aging, cancer, neurodegeneration, and atherosclerosis. One of the genes that is central to the efficient repair of this mismatch is the adenine-specific DNA glycosylase, MutY, that removes adenine at A:8-oxoG mispairs. The human MutY homolog, hMYH, has been cloned and potential polymorphic variants identified. In order to determine the functional significance of these and additional polymorphic variants in hMYH, three independent laboratories have come together with diverse but complementary expertise, to address this question. The first specific aim is to identify additional polymorphic variants in the hMYE gene and these studies will be carried out in the laboratory of H. Mohrenweiser. The choice of samples will be a subset of those that have been preselected by NIH as being representative of the U.S. population. All 16 exons and intron-exon junctions will be analyzed from 96 genomic DNA samples.
Specific aim 2 focuses on the structure-function analysis of native hMYH and its polymorphic variants. These studies will be guided and implemented in the laboratory of S. Lloyd, based on the investigator's biochemical and x-ray crystallographic determination of the prokaryotic MutY. The third specific aim, carried out in the laboratory of I. Boldogh, will ascertain the role that cellular oxidative stress has on the regulation and intracellular localization of hMYH. Polymorphic variants that are not affected adversely, with respect to catalysis, may be impaired in stabilization and localization. These goals will be accomplished using a multidisciplinary collaborative approach utilizing expertise in DNA repair enzymology, structure-function analysis, polymorphic screening, and cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017432-02
Application #
6169535
Study Section
Special Emphasis Panel (ZES1-JPM-B (01))
Program Officer
Mccormick, Anna M
Project Start
1999-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
2
Fiscal Year
2000
Total Cost
$268,978
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555