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、在几种形式的不可修复的DNA损伤时启动细胞凋亡以及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严重的遗传不稳定性，并导致几种遗传性和散发性癌症。缺乏MMR的肿瘤细胞对几种常见抗癌药物的细胞毒作用具有抵抗力，这突显了MMR的治疗重要性。以往的研究主要集中于在裸露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最重要的假设，即MMR的活动与核小体环境之间存在积极的相互作用和合作。这项拟议研究的目标是全面检验这一假说。我们的第一个目标是在核小体环境的背景下研究MMR的凋亡功能。我们的第二个目的是研究核小体环境对MMR失配校正功能的影响。我们的第三个目的是研究MMR的错配纠正功能和组蛋白H3-K56乙酰化在促进遗传稳定性方面的协同作用。为了实现这些目标，我们将利用我们在进行MMR的遗传、生化和分子生物学研究方面的独特专业知识。这些结果将有助于我们理解人类MMR的作用，以及使用组蛋白伴侣抑制剂来改善抗癌药物的效果的可能性。

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.