BRCA1 and the Inactive X Chromosome

BRCA1 和失活 X 染色体

• 批准号: 7020083
• 负责人: DAVID Morse LIVINGSTON
• 金额: $ 33.11万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-05 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020083
• 关键词: DNA damage; DNA footprinting; RNA interference; animal genetic material tag; brca gene; early embryonic stage; fluorescent in situ hybridization; gene induction /repression; gene interaction; gene mutation; genetic regulation; green fluorescent proteins; human genetic material tag; human tissue; immunoprecipitation; laboratory mouse; neoplasm /cancer genetics; polymerase chain reaction; protein structure function; sex chromosomes; single nucleotide polymorphism; southern blotting; tumor suppressor proteins; western blottings

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.

描述（由申请人提供）：BRCA1是一种肿瘤抑制基因，其生殖系突变可导致遗传性乳腺癌和卵巢癌。 BRCA1如何提供预防疾病的作用，以及为什么仅在某些女性雌激素靶细胞中才能在临床上显而易见，这是一个谜。在这方面，蛋白质以广泛的雄性和雌性细胞的形式表达。最近，我们观察到，女性体细胞细胞中BRCA1的一部分集中在非活性X染色体上（XI）。它的存在是必须将非编码RNA，XIST和专门组蛋白宏观组酮H2A 1.2共定位。这两个元素在胚胎发生过程中X灭活过程中都起着关键作用。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。尽管在BRCA1缺陷肿瘤细胞中均未带有相关的XIST或MH2A染色体，但是这些细胞中这些元素的丰度与其BRCA1产生的衍生物或同类物相同。因此，在研究的地方，BRCA1似乎促进了XIST和MH2A在XI上的定位，而不是指导其合成或控制其稳定性。最后，尽管存在2 X染色体，但多个人和鼠BRCA1 - / - 肿瘤仍缺乏易于检测的XI结构。该建议旨在理解这些现象的生化基础。由于BRCA1肿瘤抑制和BRCAI-> XIST/XI效应都是女性特异性过程，因此该提案还旨在了解这些现象是否联系在一起。