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Role Of The Tumor Suppressors Brca2 And Palb2 In Chromosome Damage Repair
Mutations in the BRCA2 gene engender a strong breast cancer risk and can lead to the cancer-prone disease Fanconi anemia of complementation group D1. BRCA2 mediates its tumor suppressor function by facilitating the DNA homology-directed repair of chromosome damage that is catalyzed by the Rad51 recombinase. BRCA2 interacts directly with Rad51 and promotes the assembly of the Rad51 presynaptic filament, a crucial step in the initiation of chromosome damage repair. Accordingly, BRCA2-deficient cells are impaired for homologous DNA repair due to a greatly diminished ability to assemble Rad51 repair centers upon the occurrence of DNA damage. BRCA2 associates with Rad51 via a domain within its carboxyl terminus (the CTRB domain) and independently through a series of conserved modules called the BRC repeats. Recently, phosphorylation of the CTRB domain was reported to regulate complex formation between BRCA2 and Rad51. However, the manner in which the CTRB domain and the BRC repeats functionally co-operate to seed the assembly of the Rad51 presynaptic filament has not been delineated.
BRCA2 also interacts with PALB2, mutations in which are also associated with breast cancer risk and represent the cause of Fanconi anemia of complementation group N. PALB2 is needed for the proper chromatin localization and functioning of BRCA2 and Rad51, but is poorly characterized otherwise. How PALB2 synergizes with BRCA2 in DNA repair and tumor suppression remains unknown.
The existing evidence allows me to hypothesize a functional dependency between BRCA2 and PALB2 in the mediation of homologous recombination and DNA repair reactions. In this research proposal, several molecular approaches will be employed to test this hypothesis and to gain mechanistic insights into the chromosome damage repair role of the BRCA2 and PALB2 proteins. Specifically, strategies are outlined to (1) delineate the role of the BRCA2 CTRB domain in Rad51-dependent DNA recombination reactions, and (2) purify and characterize the PALB2 protein for activities germane for its DNA repair role.
The results from my research studies will make a significant contribution toward deciphering the DNA repair and breast tumor suppression functions of BRCA2 and PALB2, and will shed mechanistic light on the link between defective homologous DNA repair and breast cancer susceptibility. Moreover, the experimental systems devised during the course of my fellowship studies will provide a valuable resource for assessing the functional consequences of cancer-associated and unclassified BRCA2 and PALB2 mutations, for facilitating the efforts of other breast cancer researchers, and potentially for devising new breast cancer therapies.
Even though mutations in the BRCA2 and PALB2 genes lead to breast cancers, relatively little is known about the molecular function of these tumor suppressors. Importantly, recent studies have identified a complex of the BRCA2 and PALB2 proteins and have linked this protein complex to the repair of damaged chromosomes by a high fidelity process called homologous recombination. In their chromosome damage repair role, the BRCA2-PALB2 complex influences the activity of the homologous recombination protein Rad51.
In this fellowship proposal, I outline studies that incorporate state-of-the-art biochemistry and electron microscopy to elucidate the biological function of BRCA2 and PALB2 in the repair of chromosome damage. The results from this multi-faceted approach will shed light on the link between defective homologous recombination and breast cancer development. Moreover, the experimental systems devised will provide a valuable resource for assessing functional consequences of cancer-associated and unclassified BRCA2 mutations, for facilitating efforts of other investigators, and potentially for devising specific breast cancer treatment therapies.