DNA mismatch repair in the nucleosomal environment

描述（由申请人提供）：DNA错配修复（MMR）通过纠正错配、启动细胞凋亡以响应几种形式的不可修复的DNA损伤和抑制同源重组来维持遗传稳定性。MMR的突变或表观遗传失活导致深刻的遗传不稳定性，并成为几种遗传性和散发性癌症的基础。缺乏MMR的肿瘤细胞抵抗几种常见抗癌药物的细胞毒性作用的事实突出了MMR的治疗重要性。以前的研究一直集中在裸DNA的背景下理解MMR，而对MMR在核小体环境中的作用知之甚少。我们的初步数据支持的总体假设，有积极的相互作用和合作之间的行动MMR和核小体环境。这项研究的目的是全面检验这一假设。我们的第一个目的是研究在核小体环境中MMR的凋亡功能。我们的第二个目标是研究核小体环境对MMR错配校正功能的影响。我们的第三个目的是研究MMR的错配校正功能和组蛋白H3-K56乙酰化在促进遗传稳定性方面的合作。为了实现这些目标，我们将利用我们在MMR的遗传，生物化学和分子生物学研究方面的独特专业知识。所获得的结果将显着有助于我们了解人类MMR的行动和使用组蛋白伴侣抑制剂，以改善抗癌药物的效果的潜力。

DESCRIPTION (provided by applicant): DNA mismatch repair (MMR) maintains genetic stability by correcting mismatches, initiating apoptosis in response to several forms of irreparable DNA damage, and suppressing homologous recombination. Mutational or epigenetic inactivation of MMR causes profound genetic instability and underlies several inherited and sporadic forms of cancer. The therapeutic importance of MMR is highlighted by the fact that tumor cells lacking MMR resist to the cytotoxic effects of several common anticancer drugs. Previous research has been focused on understanding MMR in the context of naked DNA, and little is known about the action of MMR in the nucleosomal environment. Our preliminary data support the overarching hypothesis that there is active interplay and cooperation between the actions of MMR and the nucleosomal environment. The goal of the proposed research is to comprehensively test this hypothesis. Our first aim is to investigate the apoptotic function of MMR in the context of the nucleosomal environment. Our second aim is to study the impact of the nucleosomal environment on the mismatch correction function of MMR. Our third aim is to examine the cooperation between the mismatch correction function of MMR and histone H3-K56 acetylation in promoting genetic stability. To achieve these aims we will take advantage of our unique expertise in performing genetic, biochemical, and molecular biology studies of MMR. The obtained results will significantly contribute to our understanding of the action of human MMR and the potential of using histone chaperone inhibitors for improving the effects of the anticancer drugs.