Roles for Mismatch Repair Proteins in Maintaining Genome Stability

DNA错配修复(MMR)系统用于切除DNA过程中发生的错配错误 复制。在真核生物中，MSH蛋白在碱基和碱基的背景下识别这些错误 插入/缺失失配和招募MLH复合体形成三元复合体 复制因子和Exo1通过错配位点切除新复制的DNA链。这是 然后是DNA的重新合成步骤。在大约一半的MMR基因中发现了突变 遗传性非息肉病性结直肠癌患者，强调 获得建立等位基因致病性的新的机理理解和分子工具。这 R35GM134872的多样性补充旨在为第一个- 一年级研究生。该计划侧重于将在资金中实施的两个组成部分 包括研究、培训和专业指导的时期。这项研究计划是由 学员在阅读MMR文献并与导师、共同导师和 康奈尔大学的科学家对基因组稳定性和分子进化感兴趣。实习生随后决定 重点关注MMR中关键复合体的亚单位MLH1-PMS1是如何共同进化到 执行MMR功能不同于其他MLH复合体，后者主要作用于减数分裂遗传 重组。受训人员建议确定面包师酵母PMS1基因的回复突变 部分或全部恢复与阿拉尼人先前发现的四个MLH1突变之一的兼容性 在一个品系背景下但在不同品系背景下不能提供MMR功能的实验室。结果来自 这项结合生化分析的工作有望提供对相关知识的理解 异二聚体复合体中的功能区。更重要的是，通过对地图的分析 由突变分析结合对来自一个MMR基因的共同进化区域的研究而产生 世界各地收集了1,010个面包师的酵母基因组，学员希望发展一种理解 了解MLH1和PMS1基因如何从其他MLH复合体中分离出来，从而在MMR中发挥特异性作用。 指导计划是在学员和顾问完成IDP后制定的，该IDP承认 学员的职业目标和实现这些目标所需的培训。一个个性化的计划是在那时 开发以确保学员参加由康奈尔大学提供的专业研讨会 专注于教学和科学交流，以及研究会议。时间线是 创建以监控计划的进展并评估在不同阶段的指导的有效性 在资助期。这些机会的有效性将通过每周会议进行评估 与顾问、委员会会议和小组会议一起，涉及阿拉尼实验室和其他 对校园里的基因组稳定性感兴趣的团体。

DNA mismatch repair (MMR) systems act to excise misincorporation errors that occur during DNA replication. In eukaryotes MSH proteins recognize these errors in the context of base-base and insertion/deletion mismatches and recruit MLH complexes to form ternary complexes that work with replication factors and Exo1 to excise the newly replicated DNA strand through the mismatch site. This is followed by DNA re-synthesis steps. Mutations in MMR genes have been found in about half of individuals suffering from hereditary non-polyposis colorectal cancer, underscoring the importance of obtaining new mechanistic understandings and molecular tools to establish allele pathogenicity. This diversity supplement to R35GM134872 is aimed at developing and executing a mentoring plan for a first- year graduate student. This plan focuses on two components that will be implemented in the funding period that involve research training and professional mentoring. The research plan was developed by the trainee after reading the MMR literature and initiating discussions with the mentor, co-mentor, and scientists at Cornell interested in genome stability and molecular evolution. The trainee then decided to focus on the question of how subunits of a critical complex in MMR, Mlh1-Pms1, have co-evolved to perform MMR functions in contrast to other MLH complexes, which act primarily in meiotic genetic recombination. The trainee proposes to identify reversion mutations in the baker’s yeast PMS1 gene that partially or wholly restore compatibility with one of four mlh1 mutations previously identified by the Alani laboratory that confer MMR function in one strain background but not in a divergent one. Results from this work in conjunction biochemical analyses are expected to provide an understanding of related functional areas within heterodimeric complexes. More importantly, through an analysis of the map generated by mutational analysis in conjunction with a study of co-evolving regions of MMR genes from a world-wide collection of 1,010 baker’s yeast genomes, the trainee expects to develop an understanding of how the MLH1 and PMS1 genes have diverged from other MLH complexes to specifically act in MMR. The mentoring plan was developed after the trainee and advisor completed an IDP which recognizes the trainee’s career goals and the training required to meet them. An individualized plan was then developed to ensure that the trainee attends professional workshops provided by Cornell University focused on teaching and science communication, as well as research conferences. A timeline was created to monitor progress on the plan and to assess the effectiveness of mentoring at different stages in the funding period. The effectiveness of these opportunities will be assessed through weekly meetings with the advisor, committee meetings, and group meetings that involve the Alani laboratory and other groups interested in genome stability on campus.