BRCA1 Function in Post-Damage Nuclear Foci

描述(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年残基的核蛋白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和执行其肿瘤抑制功能的能力之间存在很强的相关性，但这两者是如何联系在一起的，生化上尚不清楚。更具体地说，p220在体内必须执行哪些生化功能才能发挥其肿瘤抑制功能，以及这两组功能是如何相互联系的也是未知的。在这方面，在DSB产生后(例如，通过电离辐射)，p220迅速被吸引到这些受损的位置，并在一段时间后集中在在这些位置形成的焦点核结构(又名电离辐射诱导的FOCI=IRIF)。P220一旦集中在IRIF中发挥什么功能，以及如人们怀疑的那样，它们如何促进肿瘤抑制也是未知的。最近，我们和其他人检测到了一系列特定的生化步骤，使p220能够进入IRIF。它们涉及核多泛素结合蛋白Rap80及其相关的去泛素酶BRCC36的活性，以及作为p220和Rap80之间桥梁的核蛋白Abraxas的活性。所有人都在IRIF集中，并参与共集中P220。这一建议旨在：a)破译将Rap80与IRIF捆绑在一起的特定生化事件；b)了解与IRIF中p220浓度相关的功能意义；以及c)了解这些事件以何种方式与p220抑癌功能的执行有关。

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.