BRCA1 and the Inactive X Chromosome

描述(申请人提供)：BRCA1是一种肿瘤抑制基因，其胚系突变可导致遗传性乳腺癌和卵巢癌。BRCA1如何发挥其预防疾病的作用，以及为什么它们在临床上只在女性选定的雌激素靶细胞中表现出来，这是一个谜。在这一点上，该蛋白在增殖的雄性和雌性细胞中广泛表达。最近，我们观察到，在雌性体细胞中，BRCA1的一部分集中在不活跃的X染色体(XI)上。它的存在对于非编码RNA Xist和专门组蛋白Macrohistone H2A1.2的共定位是必要的。这两个元件在胚胎发育过程中的X失活过程中起着关键作用。此外，BRCA1与Xist相互作用，尽管这是否是直接相互作用尚不清楚。尽管BRCA1缺陷的肿瘤细胞中的X染色体都没有携带相关的XIST或MH2 A，但这些元素在这些细胞中的丰度与它们产生BRCA1的衍生物或对应物中的丰度相同。因此，在所研究的地方，BRCA1似乎促进了Xist和MH2 A在XI上的定位，而不是指导它们的合成或控制它们的稳定性。最后，尽管存在2X染色体，但多个人和小鼠BRCA1-/-肿瘤缺乏容易检测到的XI结构。这项建议旨在了解这些现象的生化基础。由于BRCA1肿瘤抑制和BRCA1-xist/xi效应都是女性特有的过程，该提案也旨在了解这些现象是否存在联系。

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.