DNA mismatch repair in the nucleosomal environment

核小体环境中的 DNA 错配修复

基本信息

批准号：
8439112
负责人：
Farid Kadyrov
金额：
$ 23.28万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-07 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439112
关键词：
Acetylation Antineoplastic Agents Apoptosis Apoptotic Biochemical Cells Cessation of life Chromatin Cisplatin Complex Coupled DNA DNA Damage DNA-Directed DNA Polymerase Data Daughter Defect Deposition Development Effectiveness Environment Epigenetic Process Exodeoxyribonuclease I Genetic Genetic Recombination Genetic Transcription Goals Hereditary Nonpolyposis Colorectal Neoplasms Histone H3 Histones Human Inherited Length Link MSH3 gene MSH6 gene Malignant Neoplasms Methylnitronitrosoguanidine Mismatch Repair Molecular Biology Molecular Chaperones Mutation Mutation Spectra Nucleosomes Nucleotide Excision Repair Pharmaceutical Preparations Post-Translational Protein Processing Process Relative (related person)Research Role Running Testing Therapeutic Turcot Syndrome Yeasts base cancer cell cancer therapy carcinogenesis cytotoxic design expectation fighting histone acetyltransferase homologous recombination improved inhibitor/antagonist killings neoplastic cell novel public health relevance response temozolomide

项目摘要

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.

描述（由申请人提供）：DNA不匹配修复（MMR）通过纠正不匹配，启动凋亡来响应几种形式的不可弥补的DNA损伤以及抑制同源重组来保持遗传稳定性。 MMR的突变或表观遗传失活引起深远的遗传不稳定性，并构成了几种遗传和零星的癌症形式。 MMR的治疗重要性是由于缺乏对几种常见抗癌药物的细胞毒性作用的肿瘤细胞的强调。先前的研究集中在裸体DNA的背景下理解MMR，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了以下总体假设：MMR和核小体环境的作用之间存在主动的相互作用和合作。拟议的研究的目的是全面检验该假设。我们的第一个目的是研究MMR在核小体环境中的凋亡功能。我们的第二个目的是研究核小体环境对MMR不匹配校正函数的影响。我们的第三个目的是检查MMR的不匹配校正功能与组蛋白H3-K56乙酰化在促进遗传稳定性中的合作。为了实现这些目标，我们将利用MMR的遗传，生化和分子生物学研究来利用我们独特的专业知识。获得的结果将显着有助于我们对人MMR的作用以及使用组蛋白伴侣抑制剂改善抗癌药物的作用的潜力。