Project 2: Characterizing the role of ATM and MSH2 in genome stability

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Cancer cells have mutations that alter when they will grow and die. The cells acquire these mutations through DNA damage. Normally, when a cell experiences DNA damage, DNA repair proteins are recruited to correct the damaged or mutated DNA. If the damage is not corrected, a cell death pathway is activated that kills the cell. However, mistakes in the DNA damage response can occur, resulting in the survival of cells with mutated DNA that can give rise to cancer. People who are born with mutations in genes involved in DNA repair are predisposed to developing cancer and many people not born with these mutations who develop cancer have been found to have acquired mutations in DNA repair genes in their tumors. To study how cells repair DNA damage, we use mouse B cells as a model system. To generate antibodies that recognize and eliminate pathogens, B cells are genetically programmed to mutate and delete antibody coding genes. The B cells carefully coordinate their DNA damage and DNA repair pathways to avoid triggering a cell death pathway. ATM (ataxia telangiectasia mutated) and MSH2 (MutS homologue 2) are proteins that are essential for two distinct DNA repair pathways. Mice engineered to lack either ATM or MSH2 display defects in antibody production and have a similar cancer predisposition as people born with mutations in these DNA repair genes. However, mice that lack both ATM and MSH2 are not viable (unpublished data). We hypothesize that the combined loss of ATM and MSH2 causes the accumulation of genomic DNA damage that prevents mouse development. We propose experiments to characterize the mechanism by which ATM and MSH2 cooperatively regulate genome stability and experiments to determine if these unique molecular pathways can be exploited therapeutically in cancer. The research will be led by Dr. Vuong and Dr. Chaudhuri at The City College of New York and Memorial Sloan-Kettering Cancer Center, respectively. Dr. Vuong, a former trainee of Dr. Chaudhuri, will supervise CCNY students in the proposed research, which will enhance the pipeline of underrepresented minorities trained in cancer research. The completion of the proposed research will improve the competitiveness of future grant applications from Dr. Vuong, who is a new investigator.