BRCA1 and the Inactive X Chromosome

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DESCRIPTION (provided by applicant): BRCA1 is a tumor suppressor gene, germ line mutation of which can result in inherited breast and ovarian cancer. How BRCA1 delivers its disease-preventing effects and why they are clinically apparent only in selected estrogen target cells of females is a mystery. In this regard, the protein is expressed in a wide spectrum of proliferarting male and female cells. Recently, we have observed that a fraction of the BRCA1 in female somatic cells is concentrated on the inactive X chromosomes (Xi). Its presence there is necessary for the colocalization of the noncoding RNA, Xist and the specialized histone, Macrohistone H2A 1.2. Both of these elements play a key role in the X inactivation process during embryogenesis. Furthermore, BRCA1 interacts with Xist, although whether or not this is a direct interaction remains unclear. Although neither X chromosome in BRCA1- deficient tumor cells carried associated Xist or MH2A, the abundance of these elements in such cells was the same as in their BRCA1- producing derivatives or counterparts. Hence, where studied, BRCA1 appears to promote the localization of Xist and MH2A on Xi rather than directing their synthesis or controlling their stability. Finally, multiple human and murine BRCA1 -/- tumors lack a readily detectable Xi structure despite the presence of 2 X chromosomes. This proposal is aimed at understanding the biochemical bases for these phenomena. Since both BRCA1 tumor suppression and the BRCAI->Xist/Xi effects are female-specific processes, the proposal is also aimed at learning whether these phenomena are linked.