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：
8479097
负责人：
Roger A Greenberg
金额：
$ 33.2万
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/8479097
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）：染色质修饰深刻影响 DNA 修复、肿瘤抑制和化疗反应。染色质相关 DNA 修复蛋白 BRCA1 和 53BP1 之间强大的遗传相互作用证明了染色质识别对这些现象的重要性。杂合 BRCA1 突变会增加患乳腺癌和卵巢癌的风险。 BRCA1 突变肿瘤失去了野生型等位基因，使其实际上 BRCA1 无效。因此，由于同源重组（HR）介导的DNA修复严重受损，BRCA1突变癌症在临床上对聚（ADP）核糖聚合酶抑制剂（PARPi）有反应。由于严重的基因组不稳定性，HR 受损也是 BRCA1 敲除小鼠胚胎致死的基础。引人注目的是，双无效 BRCA1-/-、53BP1-/- 小鼠存活至成年，癌症发病率并未增加，并且响应 PARPi 的径向染色体形成比 BRCA1-/-、53BP1+/+ 细胞少一个数量级。这种显着的基因拯救的发生是因为 53BP1 缺陷恢复了 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和癌症形成的原因。因此，了解差异控制 BRCA1 和 53BP1 DNA 修复功能的分子决定因素至关重要。我们提供的证据表明，组蛋白乙酰化是 BRCA1 和 53BP1 之间竞争 DNA 双链断裂 (DSB) 附近染色质积累的关键决定因素。这些发现支持一个模型，即连续组蛋白 H4 尾部乙酰化和甲基化通过将 BRCA1 和 53BP1 分离到邻近 DSB 的不同染色质区域来调节 DNA 修复机制的利用。我们将研究这些观察结果背后的分子基础，并寻求了解染色质结构和基本 DNA 修复机制之间的关系，这些机制影响对临床重要化疗药物的反应。