# Roles for Mismatch Repair Proteins in Maintaining Genome Stability

> **NIH NIH R35** · CORNELL UNIVERSITY · 2022 · $27,995

## Abstract

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.

## Key facts

- **NIH application ID:** 10619197
- **Project number:** 3R35GM134872-03S2
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Eric E. Alani
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $27,995
- **Award type:** 3
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619197

## Citation

> US National Institutes of Health, RePORTER application 10619197, Roles for Mismatch Repair Proteins in Maintaining Genome Stability (3R35GM134872-03S2). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10619197. Licensed CC0.

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