BRCA1 Function in Post-Damage Nuclear Foci

描述（由申请人提供）：BRCA1是一种肿瘤抑制基因产品，致力于抑制乳腺癌和卵巢癌的发展。它编码一个1863残基核蛋白p220。p220对多种形式的基因组完整性控制做出了贡献，其中包括通过同源重组（HR）支持双链DNA断裂（DSB）修复的能力。许多间接证据表明p220支持HR的能力与其肿瘤抑制功能之间存在很强的相关性，但这两者在生物化学上是如何联系的尚不清楚。更具体地说，p220必须执行哪些体内生化功能才能执行其肿瘤抑制功能，以及这两组功能如何相互连接也是未知的。在这方面，在产生dsb（例如通过电离辐射）后，p220被迅速吸引到这些受损部位，并在一段时间后集中在这些部位形成的焦点核结构（又称电离辐射诱导焦点=IRIF）中。p220一旦集中在IRIF中，其功能是什么，以及它们是如何促进肿瘤抑制的，这些都是未知的。最近，我们和其他人发现了一系列特定的生化步骤，这些步骤允许p220进入IRIF。它们涉及核多泛素结合蛋白Rap80，其相关的去泛素酶BRCC36，以及作为p220和Rap80之间桥梁的核蛋白Abraxas的活性。全部集中在IRIF，并参与共集中p220。该提案旨在：a)破译连接Rap80和IRIF的特定生化事件；b)了解与IRIF中p220浓度相关的功能意义；c)了解这些事件以何种方式与p220癌症抑制功能的执行相关。公共卫生相关性：BRCA1是一种乳腺癌和卵巢癌基因。当它以突变状态遗传时，女性患上述一种或两种疾病的风险要比正常情况高得多。这一提议旨在了解BRCA1如何在细胞核内发挥作用，以及为什么当其功能因突变而出现缺陷时，癌细胞就会发展。

DESCRIPTION (provided by applicant): BRCA1 is a tumor suppressor gene product dedicated to the suppression of breast and ovarian cancer development. It encodes an 1863 residue nuclear protein, p220. p220 makes contributions to multiple forms of genome integrity control, among which is an ability to support the repair of double strand DNA breaks (DSB) by homologous recombination (HR). Much circumstantial evidence suggests a strong correlation between the ability of p220 to support HR and to perform its tumor suppression function, but how the two are connected, biochemically, is unknown. More specifically, what in vivo biochemical functions p220 must execute to perform its tumor suppressing function and how the two sets of functions are connected to one another are also unknown. In this regard, after the generation of DSBs (e.g. by ionizing radiation), p220 is rapidly attracted to these damaged sites and, some time later, concentrates in focal nuclear structures (aka Ionizing Radiation Induced Foci=IRIF) that form at these locations. What functions p220 performs, once concentrated in IRIF, and how, as is suspected, they contribute to tumor suppression are also unknown. Recently, we and others detected a series of specific biochemical steps that allow p220 to gain access to IRIF. They involve the activities of a nuclear, polyubiquitin-binding protein, Rap80, its associated deubiquitinase, BRCC36, and Abraxas, a nuclear protein that serves as a bridge between p220 and Rap80. All concentrate in IRIF and participate in co-concentrating p220. This proposal is aimed at: a) deciphering the specific biochemical events that tether Rap80 to IRIF; b) at understanding the functional significance associated with p220 concentration in IRIF; and c) learning in what ways these events relate to the execution of p220 cancer suppression function. PUBLIC HEALTH RELEVANCE: BRCA1 is a breast and ovarian cancer gene. When it is inherited in a mutated state, women experience a much higher than normal risk of developing one or both of these diseases. This proposal is aimed at understanding how BRCA1 functions inside the nucleus of cells and why, when its function is rendered defective by mutation, cancer cells develop.