In this application are proposed experiments aimed at a better understanding of the breast cancer suppression function of the tumor suppressor gene product, BRCA1. In particular, we have found that the protein plays a significant role in the processes that allow post-mitotic chromatin to replicate in the next S phase, and the proposal describes experiments using Xenopus BRCA1 that are aimed at understanding the biochemical basis for this phenomenon. Furthermore, the BRCA1 gene is large and encodes multiple, alternatively spliced mRNAs. The product of one of them, a 1399 residue chromatin associated protein called IRIS is of special interest. Unlike the full length BRCA1 protein, p220, IRIS appears to facilitate S phase progression, and the proposal describes experiments aimed at understanding how this function is performed and also at whether IRIS plays a role in the evolution of certain BRCA1 -/- human tumors. Finally, we have discovered a novel DNA helicase, BACH1, as a directly interacting BRCAl-associated partner protein. BACH1/BRCA1 complex formation is essential for the development of proper double strand break repair in cells exposed to ionizing radiation, and it may well be the product of a human cancer gene in its own right. The proposal is aimed at a better understanding of how BACH 1 functions in vivo and at gaining insights into the possibility that BACH1 operates as a breast cancer suppressing element through its interaction with BRCA1.
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