The overall goal of this proposed project is to understand the mechanism of regulation of human BRCA2 gene expression in order to explore the possibility of epigenetic malformation in this mechanism, which may lead to sporadic breast cancer. Recently, we have found an Alu-repeat containing transcriptional silencer at the upstream of human BRCA2 gene. This silencer is active only in the quiescent cells but not in the dividing breast cells. The mechanisms of the activation and inactivation of this silencer in the quiescent and dividing cells, respectively, are presently unknown. We have shown that specific nuclear proteins from quiescent breast cell nuclear extract sequence-specifically binds to this silencer. Understanding the structure-activity relationships in these bindings in reference to covalent modifications of the DNA elements and the protein factors may reveal the mechanisms of the regulation of the silencer function. Our hypothesis is that the human BRCA2 gene is silenced in the quiescent stage of breast cells but is activated in the dividing cells by the inactivation of an Alu-containing silencer located at the upstream of the BRCA2 gene promoter. Possible transient epigenetic malfunction in this silencer inactivation process by environmental factors in the dividing breast cells may lead to defect in DNA repair and subsequence onset of mutations in any key gene leading to oncogenesis. We are proposing the following specific aims to test this hypothesis: (1) To identify regulatory elements in the transcriptional silencer present in the upstream of human BRTCA2 gene promoter. (2) To characterize the silencer binding proteins from breast cell nuclear extract. (3) To evaluate the effects of transient ablation of BRCA2 gene expression in replication, mutagen sensitivity and genetic stability in dividing breast cells as compared to quiescent breast cells.
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