DNA mismatch repair (MMR) is the major pathway of mutation avoidance in all organisms. Defects in human MMR genes have been directly linked to the development of cancer including hereditary nonpolyposis colorectal cancer. The striking sequence homology between bacterial and eukaryotic MMR proteins indicates that exploring bacterial MMR will advance our understanding of the regulation of mutation avoidance, genome stability and cancer development. Bacillus subtilis, a well-developed system for protein localization experiments, will be used as a model organism for MMR because like eukaryotes it does not employ dam-directed methylation for DNA strand discrimination. This work will characterize the localization of the B. subtilis MMR proteins MutS and MutL to DNA mismatches in vivo. I will monitor the localization of wild type and mutant MutS fused to green fluorescent protein (GFP). I will examine the interaction of MutS mutant proteins with the bacterial processivity factor, the beta subunit of DNA polymerase III, and their participation in strand discrimination. Other experiments will seek to identify accessory proteins that participate in MMR. This work will reveal the careful orchestration of MMR within the framework of a living cell.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA113124-02
Application #
7025667
Study Section
Special Emphasis Panel (ZRG1-F08 (20))
Program Officer
Myrick, Dorkina C
Project Start
2005-03-01
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Simmons, Lyle A; Goranov, Alexi I; Kobayashi, Hajime et al. (2009) Comparison of responses to double-strand breaks between Escherichia coli and Bacillus subtilis reveals different requirements for SOS induction. J Bacteriol 191:1152-61
Simmons, Lyle A; Grossman, Alan D; Walker, Graham C (2008) Clp and Lon proteases occupy distinct subcellular positions in Bacillus subtilis. J Bacteriol 190:6758-68