Research Project
8690306
DESCRIPTION (provided by applicant): Many factors are involved in biological viability, though none may be of more importance than the maintenance of genomic integrity. Within the spectrum of damaging events, a DNA double strand break (DSB) is one of the most compromising. The continued homeostasis of a DSB-inflicted cell depends on the faithful repair of such lesions, as suboptimal DSB repair leads to genomic instability characterized by genetic mutation, deletion, and/or gross chromosomal rearrangement; all hallmarks of malignant tumors. The Breast Cancer Susceptibility Protein 2 (BRCA2) is involved in mediating the repair of DSBs through direct interaction with the molecular apparatus at the center of homology-directed DSB repair, the RAD51 nucleoprotein filament. It is well known that the product of the BRCA2 gene is of great importance to the cell, as those with mutations of the gene are predisposed to cancer development. However, the underlying molecular mechanism of how the BRCA2-RAD51 interaction leads to error-free DSB repair is largely unknown. The goal of this project is to provide insight, on a molecular level, into how the interplay and dynamics of the BRCA2-RAD51 interactions contribute to DSB repair. A combination of biochemical and biophysical strategies will be used to characterize the properties of these interactions such as surface plasmon resonance and protein x-ray crystallography. PUBLIC HEALTH RELEVANCE: Exploiting cancerous cells which contain defective BRCA2 is showing to be a promising tool in cancer treatment, however this strategy is not infallible. In response to such treatment, defective BRCA2 can regain function through acquiring secondary mutation, which overcomes the drug susceptibility thus conferring drug resistant tumors. With full understanding into how BRCA2 functions on the molecular level, effective therapeutic treatment can be designed that will be able to overcome acquired BRCA2 drug resistance. Further, with a full understanding of the molecular details of BRCA2 function, more potential targets for cancer treatments will emerge.
