Mutation of the Breast Cancer 1 gene product (BRCA1) accounts for approximately 20,000 cases of inherited breast and ovarian cancers annually. An established function for BRCA1 is maintaining genomic integrity through the repair of DNA double strand breaks (DSBs). Inappropriate repair of DSBs can result in genomic instability -- including chromosomal rearrangements and deletions -- both of which are implicated in oncogenesis. BRCA1 is phosphorylated in response to DNA damage by the breast cancer suppressor checkpoint kinases ATM and CHK2, bolstering the concept that a BRCA1 dependent pathway of DNA repair is required to suppress malignancy. Preliminary data presented in this proposal supports a new model for BRCA1 function in DNA repair. DNA damage induced phosphorylation of BRCA1 by ATM and CHK2 kinases enables new, DNA damage specific associations for BRCA1. The resultant damage induced BRCA1 supercomplexes are biochemically and functionally distinct. Thus, BRCA1 and associated proteins do not function as a single entity to survey the genome as is widely accepted, but rather as an inducible network of modular units with distinct repair activities. This view may be relevant for a deeper understanding of DNA repair and tumor suppression phenotypes that occur in individuals harboring inactivating mutations in BRCA1 interacting proteins. The future directions described in this proposal will investigate a relationship between BRCA1 DNA damage checkpoint function and chromatin. Relationships between BRCA1 and chromatin structure are proposed to contribute to novel checkpoint and repair mechanisms. Through a series of mentored research and structured learning activities, this proposal seeks (1) to gain novel insights into the BRCA1 pathway of genome integrity maintenance and (2) to develop the requisite skills to become a successful, independent investigator in the field of cancer biology.
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