The recently isolated tumor suppressor genes, BRCA1 and BRCA2, appear to play key roles in preventing breast and ovarian carcinoma. Though current evidence suggests a role for both genes products in the maintenance of genome integrity and recombinational repair, the precise physiological roles of these proteins remains unclear. New evidence from the Livingston laboratory suggests that the two proteins may function in the same pathway. This proposal sets forth a series of experiments aimed at delineating the basic properties of the BRCA2 protein which, to date, has been largely unstudied.
The aim i s to analyze its basic cellular physiology, including details of its subcellular localization, its response to DNA damage, its association with other cellular proteins, and its patterns of covalent modification (i.e. phosphorylation). The focus is on aspects of BRCA2 biochemistry that probe the hypothesis that BRCA2 participates in the same pathway as BRCA1. In addition, a series of experiments is proposed to look for new functions of BRCA1 and 2 in DNA repair, transcriptional activation through cDNA microarray technology, and in V(D)J recombination. A search for a specific role of BRCA1 and BRCA2 in the biology of breast development is a third goal. By focusing on the function of these proteins, the hope is that the pathways of BRCA1 and BRCA2 action will be uncovered. Ideally, knowledge of the functions of these proteins will provide new insights into the process of solid tumor carcinogenesis, the maintenance of genome integrity, and the mechanisms sensing DNA damage and governing cell cycle checkpoint control. Ultimately, elucidation of the functions of BRCA1 and 2 could lead to a clearer picture of the pathogenesis of sporadic breast carcinoma. The long-term goal of the applicant is to contribute to the understanding of breast cancer.
The specific aims of this study are to: 1. Characterize the BRCA2 protein 2. Search for tractable assays of BRCA1 and BRCA2 function in tissue culture cells 3. Search for a specific role of BRCA1 and BRCA2 in mammary gland biology
|Silver, Daniel P; Livingston, David M (2012) Mechanisms of BRCA1 tumor suppression. Cancer Discov 2:679-84|
|Silver, D P; Livingston, D M (2001) Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. Mol Cell 8:233-43|