Enzymology Of Eukaryotic Mismatch Repair

真核错配修复的酶学

基本信息

批准号：
8403580
负责人：
PAUL LAWRENCE MODRICH
金额：
$ 43.02万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403580
关键词：
Accounting Address Apoptotic Biochemical Catalytic Domain Cells Cisplatin Clinical Collaborations Colon Carcinoma Complex DNA DNA Damage DNA biosynthesis DNA lesion DNA-Protein Interaction Defect Development Elements Enzymatic Biochemistry Event Future Genetic Genetic Recombination Human Human Characteristics Inherited Laboratories Lesion Malignant Neoplasms Mismatch Repair Mitotic Molecular Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurons Pathway interactions Pharmaceutical Preparations Phosphotransferases Predisposition Preparation Process Production Proteins Reaction Repair Complex Resistance Role Sequence Homologs Set protein Signal Transduction Somatic Cell Staging Structure Syndrome System Thioguanine Work antitumor drug base cancer therapy cytotoxic interest intergenerational prevent public health relevance repaired response transmission process tumor

项目摘要

DESCRIPTION (provided by applicant): DNA mismatch repair is a key mutation avoidance pathway that is of clinical interest for several reasons. Inactivation of mismatch repair is the cause of a common form of hereditary colon cancer and has been implicated in the development of a subset of sporadic tumors. Mismatch repair defects also have implications for cancer therapy because inactivation of the pathway renders cells resistant to the cytotoxic effects of certain anti-tumor drugs, a consequence of participation of the system in the DNA damage response. Perhaps surprisingly, mismatch repair function is also required for the production of certain mutations, such as the expansion of (CAG)n repeat sequences, the primary cause of a number of neurodegenerative diseases. By elucidating the molecular nature of human mismatch repair, we hope to understand its roles in controlling the occurrence of mutation. To this end we propose four lines of work: (1) Available information on the nature of strand-directed human mismatch repair indicates that the course of the reaction is dictated by an evolving set of protein-protein and protein-DNA interactions, and that repair events initiated by the mismatch recognition activities MutS1 and MutS2 differ in significant ways. By analyzing the nature of selected multi-protein and multi-protein-DNA complexes, we hope to further clarify the mechanisms of MutS1- and MutS2-initiated repair events. (2) The somatic expansion stage of (CAG)n neurodegenerative diseases, which depends on the mismatch repair activities MutS2 and MutL1, can occur in postmitotic cells, suggesting involvement of repair DNA synthesis in this process. The nature of processing of (CAG)n repeat elements by the human mismatch repair system will be addressed in both extract and purified systems. (3) Mismatch repair function is required for checkpoint and apoptotic responses to SN1 DNA methylators. Using a biochemical approach, we will pursue the mechanisms of MutS1- and MutL1-dependent activation of the ATR damage-signaling kinase in response to O6-methylguanine, the primary cytotoxic lesion produced by this class of drug. (4) Collaborative studies with the laboratory of Lorena Beese will address the structural basis of lesion recognition and processing by the human mismatch recognition system.

描述（由申请人提供）：DNA不匹配修复是一种关键的突变避免途径，其临床感兴趣的原因是多种原因。不匹配修复的灭活是遗传性结肠癌常见形式的原因，并且与零星肿瘤的一部分有关。不匹配修复缺陷也对癌症治疗有影响，因为该途径的失活使细胞具有对某些抗肿瘤药物的细胞毒性作用的抗性，这是该系统参与DNA损伤反应的结果。也许令人惊讶的是，产生某些突变（例如（CAG）N重复序列的扩展，这是许多神经退行性疾病的主要原因，也需要不匹配修复功能。通过阐明人不匹配修复的分子性质，我们希望了解其在控制突变发生中的作用。为此，我们提出了四种工作：（1）有关链指导的人不匹配修复性质的可用信息，表明反应的过程取决于不断发展的蛋白质 - 蛋白质蛋白质和蛋白质-DNA相互作用，而不匹配识别活性MUTS1和MUTS2在很大的方面差异。通过分析选定的多蛋白和多蛋白-DNA复合物的性质，我们希望进一步阐明MUTS1和MUTS2引发的修复事件的机制。（2）（CAG）N神经退行性疾病的体细胞扩张阶段取决于不匹配修复活性MUTS2和MUTL1，可能发生在蒙上期后细胞中，这表明在此过程中涉及修复DNA合成。人类不匹配修复系统对（CAG）N重复元素进行处理的性质将在提取系统和纯化系统中解决。（3）对SN1 DNA甲基机的检查点和凋亡响应需要错配修复功能。使用生化方法，我们将追求对ATR损伤信号激酶的MUTS1和MUTL1依赖性激活的机制，该激酶响应O6-甲基鸟嘌呤，O6-甲基鸟嘌呤是该类别药物产生的主要细胞毒性病变。（4）与Lorena Beese实验室的合作研究将解决人类不匹配识别系统病变识别和处理的结构基础。