Roles of Chromatin Modification in BRCA1 Dependent DNA Repair

染色质修饰在 BRCA1 依赖性 DNA 修复中的作用

基本信息

批准号：
8623113
负责人：
Roger A Greenberg
金额：
$ 32.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8623113
关键词：
ATP phosphohydrolase Acetylation Address Adult Affect Alleles BRCA1 Mutation BRCA1 gene Cell Line Cells Chromatin Chromatin Structure Chromosomes Clinical Complex DNA Double Strand Break DNA Repair DNA repair protein Double Strand Break Repair Elements Embryo Equilibrium Event Genetic Genomic Instability Histone Acetylation Histone H4 Histone deacetylase inhibition Histones Incidence Knockout Mice Laboratories Lysine Malignant Neoplasms Malignant neoplasm of ovary Maps Mediating Methylation Modeling Modification Molecular Mus Mutate Phenotype Poly(ADP-ribose) Polymerases Process Proteins Radial Relative (related person)Resistance Role System Tail Testing Tumor Suppression base carcinogenesis chemotherapeutic agent chemotherapy chromatin modification chromatin protein deep sequencing drug sensitivity high risk histone acetyltransferase homologous recombination inhibitor/antagonist malignant breast neoplasm mutant public health relevance recombinational repair residence response tumor

项目摘要

DESCRIPTION (provided by applicant): Chromatin modifications profoundly influence DNA repair, tumor suppression, and response to chemotherapy. A powerful genetic interaction between chromatin associated DNA repair proteins BRCA1 and 53BP1 exemplifies the importance of chromatin recognition to these phenomena. Heterozygous BRCA1 mutation confers a high risk of breast and ovarian cancer. BRCA1 mutant tumors lose the wildtype allele, rendering them effectively BRCA1 null. Consequently, BRCA1 mutant cancers respond clinically to poly(ADP)ribose polymerase inhibitors (PARPi) due to severely impaired homologous recombination (HR) mediated DNA repair. Impaired HR also underlies the embryonic lethality in BRCA1 knockout mice due to massive genomic instability. Strikingly, double null BRCA1-/-, 53BP1-/- mice survive to adulthood without increased cancer incidence, and show an order of magnitude less radial chromosome formation in response to PARPi than do BRCA1-/-, 53BP1+/+ cells. This remarkable genetic rescue occurs because 53BP1 deficiency restores HR in BRCA1 mutant cells, suggesting that inappropriate 53BP1 activity is causative for genomic instability and cancer formation in BRCA1 mutant cells. It is therefore of central importance to understand the molecular determinants that differentially control BRCA1 and 53BP1 DNA repair functions. We present evidence that histone acetylation is a critical determinant of a competition between BRCA1 and 53BP1 for accumulation at chromatin adjacent to DNA double strand breaks (DSBs). These findings support a model whereby sequential histone H4 tail acetylation and methylation regulate DNA repair mechanism utilization by segregating BRCA1 and 53BP1 to different chromatin territories adjacent to DSBs. We will investigate the molecular basi underlying these observations and seek to understand the relationship between chromatin structure and basic DNA repair mechanisms that influence responses to clinically important chemotherapeutic agents.

描述（由申请人提供）：染色质修饰深远影响DNA修复，抑制肿瘤和对化学疗法的反应。染色质相关的DNA修复蛋白BRCA1和53BP1之间的强大遗传相互作用体现了染色质识别对这些现象的重要性。杂合BRCA1突变赋予乳腺癌和卵巢癌的高风险。 BRCA1突变肿瘤失去了野生型等位基因，使它们有效地brca1 null。因此，由于严重受损的同源重组（HR）介导的DNA修复，BRCA1突变癌对聚（ADP）核糖聚合酶抑制剂（PARPI）的反应。由于基因组不稳定，HR受损的人力资源还基于BRCA1敲除小鼠的胚胎致死性。引人注目的是，双重null BRCA1 - / - ，53BP1 - / - 小鼠在成年时生存而无需增加癌症的发生率，并且比BRCA1 - / - ， - / - ，53BP1+/+细胞显示出对PARPI的径向染色体形成较小的数量级。这种显着的遗传救助之所以发生，是因为53BP1缺乏恢复了BRCA1突变细胞中的HR，这表明不适当的53BP1活性是BRCA1突变细胞中基因组不稳定性和癌症形成的原因。因此，了解分子决定因素差异控制BRCA1和53BP1 DNA修复功能是至关重要的。我们提供的证据表明，组蛋白乙酰化是BRCA1和53BP1之间竞争的关键决定因素，用于在与DNA双链断裂（DSB）附近的染色质中积累。这些发现支持了一个模型，从而通过将BRCA1和53BP1隔离到与DSBS相邻的不同染色质领土来调节DNA修复机制利用DNA修复机制。我们将研究这些观察结果的基础分子基础，并试图了解影响对临床上重要化学治疗剂的反应的染色质结构与基本DNA修复机制之间的关系。