Dissecting the role of BRCA2 in the DNA damage res.. (Dissecting BRCA2)
Dissecting the role of BRCA2 in the DNA damage response and exploiting its parts for anticancer therapy
Date du début: 1 nov. 2011,
Date de fin: 31 oct. 2015
Mutations in the tumor suppressor gene, BRCA2, cause susceptibility to breast and ovarian cancer. BRCA2 protein is required for homologous recombinational DNA repair (HRR), the predominant mechanism employed by cells to accurately repair DNA double-stranded breaks (DSBs). In humans, the central player of the HRR process is RAD51; it catalyzes the DNA strand exchange that results in the repaired DNA. Through its interaction with RAD51, BRCA2 controls RAD51 function by locating it to the DSBs. Thus, defects in BRCA2 lead to genomic instability, a hallmark of tumorigenesis.During my postdoc, I have revealed important aspects of BRCA2 protein, the regulatory function of the BRC repeats of BRCA2 on RAD51 DNA binding selectivity as well as contribute to the first biochemical characterization of the full-length BRCA2 protein.In an interdisciplinary approach and, as an independent researcher, my main goals are to:1) Reveal new roles of BRCA2 by mapping the interactions with other proteins: For example, recently a DMC1 interacting site on BRCA2 has been reported involving BRCA2 in meiotic recombination.2) Better understand the HRR process: Evidences from the BRCA2 homologue in fungus point to another DNA binding site in BRCA2; finding this region in the human protein may decipher important aspects of the regulation of HRR that remain elusive.3) Exploit regions of the protein as a therapeutic tool for tumor treatment. We will use peptides derived from BRCA2 protein that are involved in interactions with key proteins in the HRR pathway to block this pathway in tumors cells.4) Develop new strategies to carry these peptides to the targeted tumor cells.The combination of basic science (aims 1, 2) and applied science (aims 3, 4) approaches proposed here provides a framework to understand the connection between different DNA damage response mechanisms that in turn, will lead to develop new anticancer therapies.
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