BRCA1 Function in Post-Damage Nuclear Foci

 描述（由申请人提供）：BRCA 1是一种多功能乳腺癌和卵巢癌抑制基因，怀疑其通过抑制基因组疾病的发展以这种方式起作用。但它如何传递信号，引发临床癌症抑制效果， 未知在目前的授权期间，我们报告说，BRCA 1蛋白（又名B1），本身，执行至少一个由B1结合，多亚基蛋白复合物，称为RAP 80提供的严格控制下，其多种生化功能。这个更大的复合体称为RAP 80/B1复合体，它允许B1通过同源重组（HR）以正常幅度进行无错误的双链DNA断裂（DSB）修复。因此，RAP 80/B1在生理上调节B1 HR功能，这是B1癌症抑制的已知贡献者。这一过程被称为“人力资源调整”。我们还报道了存在于RAP 80/B1复合物中的另一种蛋白质，即酶PARP 1。在这些复合物中，PARP 1选择性地聚ADP核糖基化（parsylates）B1的DNA结合结构域，形成parsylated衍生物，又名B1 pars。RAP 80/B1复合物的形成和适当的B1 parsylation有助于B1 HR和B1基因组稳定性控制。所有这些事件都发生在DNA损伤后形成的专门的、含有DSB的核焦点结构（又名IRIF）中，并需要这些结构的运作。在这个提议中，我们将确定：a）PARP 1催化的B1 parsylation是否调节B1的任何其他已知功能，包括癌症抑制; B）特定PARP 1驱动的B1 parsylation如何定向到其DNA结合结构域; c）B1 parsylation和RAP 80/B1 pars复合物形成的缺陷是否引起散发性乳腺癌和卵巢癌发展的临床重要贡献;以及d）它们是否指示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.