Our long term goal is to understand the biology, the biochemistry and the genetics of how cells protect themselves against the deleterious effects of DNA damage, with particular emphasis upon the mechanisms cells employ to protect against DNA damage derived from endogenous cellular compounds. For the most part our studies involve investigating how cells protect themselves against DNA alkylation damage, but we will also examine how cells protect themselves against DNA oxidative damage. The mechanisms that cell employ to defend against DNA damaging agents have been highly conserved, and we now know that bacteria yeast and human cells employ similar strategies to repair DNA damage. Our research in the last grant period led us into studies on spontaneous mutation in both prokaryotes and eukaryotes; further studies on spontaneous mutation in eukaryotes is the main focus of this application. The plan was designed to encompass research at various levels of development; i.e., from further characterizing pathways already known to affect spontaneous mutation to identifying new pathways that affect spontaneous mutation. This purposefully broad-based plan results in a diverse proposal which I believe is compatible and complementary to-the other projects in this program, and which I believe will enhance our understanding of spontaneous mutation in eukaryotes.
The specific Aims i nclude the following: explore the role that DNA repair methyltransferases play in limiting spontaneous mutation; determine whether the natural metabolite S-adenosylmethionine produces spontaneous DNA damage that can lead to spontaneous mutations; explore the role that 3-methyladenine DNA glycosylases enzymes play in generating spontaneous abasic sites which can lead to spontaneous mutation; explore the proposed interaction between the DNA mismatch repair pathway and DNA alkylation damage; isolate and characterize new S. cerevisiae mutator strains that are compromised in their ability to deal with oxidative damage to DNA and DNA precursors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES003926-13
Application #
6106119
Study Section
Project Start
1997-09-01
Project End
1999-08-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Memisoglu, A; Samson, L (2000) Contribution of base excision repair, nucleotide excision repair, and DNA recombination to alkylation resistance of the fission yeast Schizosaccharomyces pombe. J Bacteriol 182:2104-12
Wyatt, M D; Samson, L D (2000) Influence of DNA structure on hypoxanthine and 1,N(6)-ethenoadenine removal by murine 3-methyladenine DNA glycosylase. Carcinogenesis 21:901-8
Opperman, T; Murli, S; Smith, B T et al. (1999) A model for a umuDC-dependent prokaryotic DNA damage checkpoint. Proc Natl Acad Sci U S A 96:9218-23
Hickman, M J; Samson, L D (1999) Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Proc Natl Acad Sci U S A 96:10764-9
Li-Sucholeiki, X C; Khrapko, K; Andre, P C et al. (1999) Applications of constant denaturant capillary electrophoresis/high-fidelity polymerase chain reaction to human genetic analysis. Electrophoresis 20:1224-32
Bennett, R A (1999) The Saccharomyces cerevisiae ETH1 gene, an inducible homolog of exonuclease III that provides resistance to DNA-damaging agents and limits spontaneous mutagenesis. Mol Cell Biol 19:1800-9
Ekstrom, P O; Borresen-Dale, A L; Qvist, H et al. (1999) Detection of low-frequency mutations in exon 8 of the TP53 gene by constant denaturant capillary electrophoresis (CDCE). Biotechniques 27:128-34
Glassner, B J; Posnick, L M; Samson, L D (1998) The influence of DNA glycosylases on spontaneous mutation. Mutat Res 400:33-44
Glassner, B J; Rasmussen, L J; Najarian, M T et al. (1998) Generation of a strong mutator phenotype in yeast by imbalanced base excision repair. Proc Natl Acad Sci U S A 95:9997-10002
Masuda, Y; Bennett, R A; Demple, B (1998) Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product. J Biol Chem 273:30352-9

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