Enzymology Of Eukaryotic Mismatch Repair

真核错配修复的酶学

基本信息

批准号：
8599467
负责人：
PAUL LAWRENCE MODRICH
金额：
$ 44.58万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599467
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 错配修复是一种关键的突变避免途径，由于多种原因而引起临床关注。错配修复失活是遗传性结肠癌常见形式的原因，并且与散发性肿瘤亚型的发展有关。错配修复缺陷也对癌症治疗产生影响，因为该途径的失活使细胞对某些抗肿瘤药物的细胞毒性作用产生抵抗力，这是系统参与 DNA 损伤反应的结果。也许令人惊讶的是，某些突变的产生也需要错配修复功能，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。通过阐明人类错配修复的分子本质，我们希望了解其在控制突变发生中的作用。为此，我们提出了四项工作：（1）关于链定向人类错配修复性质的现有信息表明，反应过程是由一组不断发展的蛋白质-蛋白质和蛋白质-DNA相互作用决定的，并且由错配识别活动启动的修复事件 MutS1 和 MutS2 有显着差异。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启动的修复事件的机制。 (2) (CAG)n 神经退行性疾病的体细胞扩张阶段依赖于错配修复活性 MutS2 和 MutL1，可发生在有丝分裂后细胞中，表明修复 DNA 合成参与了这一过程。人类错配修复系统处理 (CAG)n 重复元件的性质将在提取物和纯化系统中得到解决。 (3) SN1 DNA 甲基化的检查点和细胞凋亡反应需要错配修复功能。使用生化方法，我们将探究 ATR 损伤信号激酶响应 MutS1 和 MutL1 依赖性激活的机制，O6-甲基鸟嘌呤是此类药物产生的主要细胞毒性损伤。 (4) 与Lorena Beese实验室的合作研究将解决人类错配识别系统识别和处理病变的结构基础。