BRCA1 Function in Post-Damage Nuclear Foci

 描述(申请人提供)：BRCA1是一种多功能的乳腺癌和卵巢癌抑制基因，它被怀疑通过抑制基因组紊乱的发展而以这种方式发挥作用。但它是如何传递信号来产生临床癌症抑制效果的 未知。在目前的授权期内，我们报告了BRCA1蛋白(又名B1)本身在被称为RAP80的B1结合的多亚单位蛋白复合体的严格控制下至少执行其多种生化功能中的一种。这个更大的复合体被称为RAP80/B1复合体，它允许B1在正常幅度下通过同源重组(HR)进行无错误的双链DNA断裂(DSB)修复。因此，RAP80/B1在生理上调节B1HR功能，这是一种已知的对B1癌症抑制的贡献者。这个过程被称为“人力资源调整”。我们还报道了RAP80/B1复合体中存在另一种蛋白质，即PARP1酶。在这些复合体中，PARP1选择性地将多聚ADP核糖化(PARPATE)B1的DNA结合域，形成PARP1的PARP衍生物，又名B1pars。RAP80/B1复合体的形成和适当的B1副糖化有助于控制B1、HR和B1基因组的稳定性。所有这些事件都发生在特殊的、含有DSB的核焦点结构(又名IRIF)中，这些结构在DNA损伤后形成，需要进行手术。在这项提案中，我们将确定：a)PARP1催化的B1糖基化是否调节B1的任何其他已知功能，包括抑制癌症；b)PARP1驱动的B1糖基化是如何针对其DNA结合区域的；c)B1糖基化和RAP80/B1pars复合体形成的缺陷是否会导致散发性乳腺癌和卵巢癌的临床重要贡献；以及d)它们是否决定了实现有效的乳腺癌和卵巢癌治疗的特定策略。

 DESCRIPTION (provided by applicant):BRCA1 is a multi-functional breast and ovarian cancer suppression gene that is suspected of operating in this manner by suppressing the development of genome disorder. But how it delivers signals that elicit a clinical cancer suppressing effect is unknown. During the current granting period, we reported that the BRCA1 protein (aka B1), itself, executes at least one of its multiple biochemical functions under tight control afforded bya B1-bound, multi-subunit protein complex, called RAP80. This larger complex is called the RAP80/B1 complex, and it allows B1 to perform at normal amplitude error-free double strand DNA break (DSB) repair by homologous recombination(HR). Thus, RAP80/B1 physiologically regulates B1 HR function, which is a known contributor to B1 cancer suppression. This process is termed `HR tuning'. We have also reported that there is another protein present in RAP80/B1 complexes, i.e. the enzyme PARP1. In these complexes, PARP1 selectively poly-ADP ribosylates (parsylates) the DNA binding domain of B1 to form a parsylated derivative, aka B1pars. RAP80/B1 complex formation and proper B1 parsylation contribute to B1 HR and B1 genome stability control. All of these events take place in and require the operation of specialized, DSB- containing nuclear focal structures (aka IRIF) that form after DNA damage. In this proposal, we will determine: a) whether PARP1-catalyzed B1 parsylation regulates any of the other, known functions of B1, including cancer suppression; b) how the specific PARP1-driven parsylation of B1 is directed to its DNA binding domain; c) whether defects in B1 parsylation and RAP80/B1pars complex formation elicit clinically important contributions to sporadic breast and ovarian cancer development; and d) whether they dictate a specific strategy for achieving effective breast and ovarian cancer therapy.