Roles of Chromatin Modification in BRCA1 Dependent DNA Repair

描述（由申请人提供）：染色质修饰深刻影响DNA修复、肿瘤抑制和对化疗的反应。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。杂合子BRCA1突变具有较高的乳腺癌和卵巢癌风险。BRCA1突变肿瘤失去了野生型等位基因，使其有效地为BRCA1零。因此，由于同源重组（HR）介导的DNA修复严重受损，BRCA1突变型癌症在临床上对聚（ADP）核糖聚合酶抑制剂（PARPi）有反应。由于大量的基因组不稳定，HR受损也是BRCA1基因敲除小鼠胚胎致命性的基础。引人注目的是，双空BRCA1-/-， 53BP1-/-小鼠存活到成年后没有增加癌症发病率，并且在PARPi的反应中显示出比BRCA1-/-， 53BP1+/+细胞少数量级的径向染色体形成。这种显著的基因拯救发生是因为53BP1缺陷恢复了BRCA1突变细胞的HR，这表明不适当的53BP1活性是BRCA1突变细胞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在DNA双链断裂（DSBs）附近染色质积累竞争的关键决定因素。这些发现支持了一个模型，即序列组蛋白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，并试图了解染色质结构和影响临床重要化疗药物反应的基本DNA修复机制之间的关系。

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.