Roles for Mismatch Repair Proteins in Maintaining Genome Stability

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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.