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Multi-scale imaging of breast cancer proteins during DNA repair

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Abstract Mutations in the breast cancer susceptibility protein, BRCA1, are heavily linked to the development of triple negative breast and ovarian cancers. Currently, there are no precise treatments to mitigate the detrimental effects of BRCA1 mutations in triple negative cancer patients and recurrence rates for this disease are higher than in any other form of breast cancer. At the molecular level, wild type BRCA1 helps protect the genome by its involvement in DNA repair processes, thus serving as a tumor suppressor. However, cells harboring BRCA1 mutations lose the ability to properly repair DNA damage and transcribe their genome. The culmination of these events leads to genomic instability and eventually cancer induction. The precise manner in which mutated BRCA1 fails to execute its functions remains unclear. Decoding the molecular mechanisms for these defects could provide significant insight into cancer susceptibilities for individuals harboring BRCA1 mutations. Based on our preliminary data derived from biochemical experiments, cryo-Electron Microscopy (EM) imaging, and molecular modeling routines, we believe disease penetrance or severity is related to the position of mutations in the BRCA1 protein sequence. Simply stated, mutations in BRCA1 that affect its ability to associate with other proteins during gene expression can lead to increases in DNA damage, genomic instability, and cancer induction. As such, our objective is to determine how BRCA1 interacts with other key proteins to ensure proper RNA production ? and to understand how mutations in the BRCA1 gene impact these events. We predict that clinical mutations in BRCA1 will reduce its affinity for its binding partners BARD1 and RNA Polymerase II (RNAP II). These limited interactions will thereby diminish BRCA1?s capacity to monitor DNA and coordinate repair mechanisms. We will use a unique combination of experimental and computational approaches to test these ideas. By implementing a molecular-based strategy to delineate the multifaceted role of BRCA1 in RNA metabolism, we expect to define new opportunities to better manage diseases conditions for individuals faced with BRCA1 genetic susceptibility.
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