Molecular Mechanisms of BRCA1-Dependent DNA Damage Response and Tumorogenesis

BRCA1 依赖性 DNA 损伤反应和肿瘤发生的分子机制

基本信息

批准号：
9269160
负责人：
Xiaochun Yu
金额：
$ 38.25万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269160
关键词：
Acetyltransferase Affinity Chromatography Area BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Basic Science Biochemical Biological Assay C-terminal Cancer Etiology Cancer Patient Cancer-Predisposing Gene Cell physiology Cells Chromatin Chromosomal Instability Complex DNA Binding DNA Damage DNA Double Strand Break DNA Repair DNA lesion DNA-Binding Proteins Defect Genome Stability Genomic Instability Genotoxic Stress Germ-Line Mutation Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases HTATIP gene Hereditary Breast Carcinoma Hereditary Disease Histone Acetylation Histone Deacetylase Inhibitor Histone H4 Hypersensitivity Impairment In Vitro Induced Mutation Knowledge Lead Link Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Molecular Mutation N-terminal Normal Cell Nuclear Pathway interactions Physical condensation Play Prevention Property Proteins Relaxation Reporting Research Role Site Testing Translating Tumor Suppression Tumor Suppressor Proteins WD Repeat chromatin remodeling design ds-DNA genome integrity hazard homologous recombination in vivo inhibitor/antagonist irradiation malignant breast neoplasm mutation carrier novel novel strategies novel therapeutics ovarian neoplasm polypeptide prevent public health relevance recombinational repair repaired response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): BRCA1 and BRCA2 are nuclear polypeptides to suppress familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response and maintain genomic stability. Mutations of BRCA1 and BRCA2 abrogate DNA damage repair and cause genomic instability under genotoxic stress, which eventually induces tumorigenesis. However, the molecular mechanism by which BRCA1 and BRCA2 participate in DNA damage response remain elusive, which impairs the irradiation of familial breast and ovarian cancers. Recently, we and others identified that PALB2 is an important adaptor that links BRCA1 and BRCA2 in a linear DNA damage repair pathway. Moreover, like BRCA1 and BRCA2, germline mutations of PALB2 are associated with familial breast and ovarian cancers, suggesting that PALB2 is a bona fide tumor suppressor. To elucidate the function of this BRCA pathway in DNA damage response and tumor suppression, our research focuses on the molecular mechanism of PALB2. Using unbiased protein affinity purification approach, we identified several PALB2 partners. Our preliminary study indicates that PALB2 is a double-strand DNA binding protein and plays an important role in DNA damage-induced histone acetylation and chromatin remodeling. In this project, we plan to: 1) dissect the molecular mechanism of PALB2 in DNA damage-induced chromatin remodeling; 2) examine the functional defects of cancer-associated PALB2 mutations; 3) explore novel therapeutic strategies to prevent PALB2 deficiency-induced tumorigenesis. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our knowledge from basic science research into tumor prevention.

描述（由申请人提供）：BRCA1和BRCA2是抑制家族性乳腺癌和卵巢癌的核多肽。积累的证据表明，BRCA1和BRCA2都参与DNA损伤反应并保持基因组稳定性。 BRCA1和BRCA2的突变消除了DNA损伤修复并在遗传毒性应激下引起基因组不稳定，最终诱导肿瘤发生。但是，BRCA1和BRCA2参与DNA损伤反应的分子机制仍然难以捉摸，这会损害家族性乳腺癌和卵巢癌的照射。最近，我们和其他人确定PALB2是一个重要的适配器，它将BRCA1和BRCA2连接到线性DNA损伤修复途径中。此外，例如BRCA1和BRCA2，PALB2的种系突变与家族性乳腺癌和卵巢癌有关，这表明PALB2是一种真正的肿瘤抑制剂。为了阐明该BRCA途径在DNA损伤反应和肿瘤抑制中的功能，我们的研究集中于PALB2的分子机制。使用无偏的蛋白质亲和力纯化方法，我们确定了几个PALB2伴侣。我们的初步研究表明，PALB2是双链DNA结合蛋白，在DNA损伤诱导的组蛋白乙酰化和染色质重塑中起着重要作用。在该项目中，我们计划：1）在DNA损伤诱导的染色质重塑中剖析PALB2的分子机制； 2）检查与癌症相关的PALB2突变的功能缺陷； 3）探索预防PALB2缺乏诱导的肿瘤发生的新型治疗策略。这些研究不仅会揭示DNA损伤反应中BRCA途径的分子机制，而且还将我们的知识从基础科学研究转化为预防肿瘤。