Breast cancer accounts for a staggering 32% of the total number of new cancer cases diagnosed in American women each year. Up to 10% of these cases are caused by mutations on the tumor suppressor gene BRCA1. The physiological and biochemical function of BRCA1 in normal cells remains elusive. The recently described BACH1 DNA helicase functions together with BRCA1 to mediate efficient repair of double strand breaks. The proposal hypothesizes that the DNA repair and tumor suppression functions of BRCA1 are intimately linked to BACH1 function and that BACH 1 is the product of a cancer gene itself. In order to elucidate the biological properties of BACH1, we are utilizing a combination of biochemistry, mammalian cell culture, and murine models. Preliminary results strongly suggest that BACH1 participates in the response to DNA damage. Like BRCA1, BACH1 is modified upon DNA damage by phosphorylation, an event that is critical for its activity as a DNA mechanic. Moreover, disease-associated sequence alterations in the BACH1 coding region result in defective helicase enzymes, providing a biochemical link between BACH1 activity and disease development. Specifically, the project aims to: 1) define the role of BACH1 in cellular proliferation and DNA repair; 2) examine the nature and significance of post-DNA damage induced BACH1 phosphorylation on BACH1 biological function; and 3) assess whether BACH1 is the product of a cancer gene. The long-term goals are to better understand the connection between genome integrity control and oncogenesis. Dr. Ronny Drapkin, the principal investigator, is an M.D., Ph.D., who has completed residency training in anatomic pathology, and wishes to develop an independent research career focusing on oncogenic events in cancer development and progression. The sponsor, Dr. David Livingston, is a recognized world-leader in cancer biology with a strong record of training successful basic investigators.
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