BRCA1 Function in Post-Damage Nuclear Foci

BRCA1 在损伤后核病灶中的功能

基本信息

批准号：
9196343
负责人：
DAVID Morse LIVINGSTON
金额：
$ 51.55万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196343
关键词：
ADP ribosylation Address Affect BACH1 gene BARD1 gene BRCA1 Protein BRCA1 gene Binding Binding Proteins Biochemical Biological Breast Cancer Detection Cell Line Cells Charge Chromatin Chromosomal Stability Clinical Complex Congenital chromosomal disease DNA Binding DNA Binding Domain DNA Damage DNA Double Strand Break DNA Repair Defect Development Diagnosis Disease Double Strand Break Repair Enzymes Event Excision Fostering Gamma-H2AX Genes Genetic Recombination Genome Genome Stability Germ Lines Grant Human Inherited Ionizing radiation Learning Maintenance Malignant Neoplasms Malignant neoplasm of ovary Methods Nuclear Nuclear Structure Organ Outcome Performance Phenocopy Physiological Poly(ADP-ribose) Polymerases Process Protein Complex Subunit Proteins Regulation Reporting Signal Transduction Site Structure Suppressor Genes Surface Tissues Tumor Suppressor Genes Woman Xenograft procedure base cancer therapy clinical effect clinically significant genome integrity homologous recombination loss of function mutation malignant breast neoplasm novel strategies operation polypeptide prevent public health relevance recombinational repair repaired response success targeted treatment tumor ubiquitin-protein ligase

项目摘要

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.

描述（由应用程序提供）：BRCA1是一种多功能乳腺癌和卵巢癌抑制基因，怀疑通过抑制基因组疾病的发展而以这种方式进行操作。但是，它如何提供引起临床癌症抑制效果的信号是未知。在当前的授予期间，我们报告说，BRCA1蛋白（又称B1）本身在紧密控制下执行其多种生化功能之一，由YAY B1结合，多生育蛋白复合物（称为RAP80）。这种较大的复合物称为Rap80/B1复合物，它允许B1通过同源重组（HR）在无通用的双链DNA断裂（DSB）修复下进行正常放大器的执行。这是RAP80/B1物理调节B1 HR功能，这是抑制B1癌症的已知贡献者。此过程称为“人力资源调整”。我们还报告说，Rap80/B1复合物（即酶PARP1）中存在另一种蛋白质。在这些复合物中，PARP1选择性地聚ADP核糖基（Parsylates）B1的DNA结合结构域形成了圆锥体的衍生物，也就是B1pars。 RAP80/B1复合物的形成和适当的B1阶层有助于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，含有核焦点结构（又名IRIF）的专用DSB的运行。在此提案中，我们将确定：a）pARP1催化的B1泊合作是否可以调节B1的其他任何已知功能，包括癌症的抑制作用； b）B1的特定PARP1驱动的Parsylation如何针对其DNA结合结构域； c）B1荒原和Rap80/B1pars复合物的缺陷是否对零星乳腺癌和卵巢癌发育产生了重要的临床贡献； d）它们是否决定实现有效乳腺癌和卵巢癌疗法的特定策略。