Functional analysis of BRCA1 in DNA damage response and tumor suppression

BRCA1在DNA损伤反应和肿瘤抑制中的功能分析

基本信息

批准号：
8747748
负责人：
Xiaochun Yu
金额：
$ 32.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747748
关键词：
Address Architecture BARD1 gene BRCT Domain Basic Science Benign Binding Binding Proteins Breast C-terminal Cancer Patient Cancer-Predisposing Gene Cell Cycle Cell Cycle Checkpoint Cell physiology Cells Chromosomal Instability Clinical Trials Complex DNA Damage DNA Double Strand Break DNA Repair DNA lesion Defect Double Strand Break Repair Genetic Polymorphism Genome Genome Stability Genomic Instability Genotoxic Stress Germ-Line Mutation Health Hereditary Breast Carcinoma Induced Mutation Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mediating Molecular Mutation Nuclear Pathway interactions Patients Play Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Prevention Research Role Site Translating Tumor Suppression Tumor Suppressor Proteins base coping hazard in vivo inhibitor/antagonist killings malignant breast neoplasm mutation carrier neoplastic cell ovarian neoplasm polypeptide research study response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): BRCA is an important tumor suppressor for familiar breast and ovarian cancers. Accumulated evidence suggests that BRCA1 participates in DNA damage response including cell cycle checkpoint activation and DNA damage repair. Mutations of BRCA1 abrogate DNA damage response and induce genomic instability under genotoxic stress. Interestingly, recent evidence suggests that PARP inhibitors can specifically suppress BRCA1 mutation-induced breast tumors. Again, the molecular mechanism by which PARP inhibitor selectively kill tumor cells bearing BRCA1 mutations is not clear. It has been shown that BARD1 is a functional partner of BRCA1. Like BRCA1, germline mutations of BARD1 have been found in breast and ovarian cancer patients. Carriers of BARD1 mutations are also predisposed to breast and ovarian cancers, suggesting that like BRCA1, BARD1 is an important tumor suppressor. Unexpectedly, we found that the BRCT domain of BARD1 recognizes poly(ADP-ribose) (PAR). The interaction between the BARD1 BRCT domain and PAR is required for targeting BRCA1 to the sites of DNA damage and facilitates the correlated DNA damage repair. Based on our preliminary study, we hypothesize that the binding between PAR and the BRCA1-BARD1 complex plays a critical role for breast and ovarian tumor suppression. Thus, in this project, we plan to: 1) examine the molecular mechanism by which PAR regulates the BRCA1-BARD1 complex in response to DNA damage; 2) characterize the functional defects of the cancer-associated BRCA1 and BARD1 mutations in PAR-dependent DNA damage response; 3) study the efficacy of PARP inhibitors in the treatment of BRCA1 mutation-induced mammary tumors. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our basic science research into tumor prevention.

描述（由申请人提供）：BRCA是熟悉的乳腺癌和卵巢癌的重要肿瘤抑制剂。积累的证据表明，BRCA1参与DNA损伤反应，包括细胞周期检查点激活和DNA损伤修复。 BRCA1的突变消除了DNA损伤反应并在遗传毒性应激下诱导基因组不稳定。有趣的是，最近的证据表明，PARP抑制剂可以特异性抑制BRCA1突变诱导的乳腺肿瘤。同样，PARP抑制剂选择性杀死带有BRCA1突变的肿瘤细胞的分子机制尚不清楚。已经表明，Bard1是BRCA1的功能合作伙伴。像BRCA1一样，在乳腺癌和卵巢癌患者中发现了Bard1的种系突变。 Bard1突变的载体也倾向于乳腺癌和卵巢癌，这表明像BRCA1一样，Bard1是重要的肿瘤抑制剂。出乎意料的是，我们发现BARD1的BRCT结构域识别Poly（ADP-核糖）（PAR）。将BRCT域与PAR之间的相互作用是将BRCA1靶向DNA损伤部位并促进相关DNA损伤修复所必需的。基于我们的初步研究，我们假设PAR和BRCA1-BARD1复合物之间的结合对于乳腺癌和卵巢肿瘤抑制至关重要。因此，在这个项目中，我们计划：1）检查分子机制，该机制对DNA损伤响应于DNA损伤来调节BRCA1-BARD1复合物； 2）表征与癌症相关的BRCA1和BARD1突变的功能缺陷； 3）研究PARP抑制剂对BRCA1突变诱导的乳腺肿瘤的疗效。这些研究不仅会揭示DNA损伤反应中BRCA途径的分子机制，而且还将我们的基础科学研究转化为预防肿瘤。