# Roles for Mismatch Repair Proteins in Maintaining Genome Stability

> **NIH GM R35** · CORNELL UNIVERSITY · 2026 · $430,989

## Abstract

Mismatch repair (MMR) factors, which act to remove DNA replication misincorporation errors, also function in
genetic recombination and in adaptation to stress. The latter two roles are the current focus of my research
efforts. Research Area 1 is centered on crossing over, a process critical in most eukaryotes for the accurate
segregation of homologous chromosomes in meiosis to form gametes. Most crossovers in baker’s yeast meiosis
result from the biased resolution of double Holliday Junction (dHJ) intermediates in steps involving Exo1 and the
Mlh1-Mlh3 MMR endonuclease, a process conserved in higher eukaryotes. Little is known about how seemingly
symmetric dHJs are resolved in a biased manner. We developed a model to explain biased dHJ resolution in
which the Exo1 protein protects nicks in or near dHJs from being ligated; this protection promotes subsequent
resolution by the Mlh1-Mlh3 endonuclease. We are testing it by developing a method in yeast to map meiotic
DNA nicks genome-wide in wild-type, exo1, and other mutant backgrounds. The data will be analyzed in
combination with Exo1 chromatin localization maps and established maps for meiotic chromatin marks and
double-strand break sites to obtain a model for crossover resolution that will be refined through analyses of
mutants displaying defects in early to late steps of meiotic recombination. Area 2 focuses on an analysis of
baker’s yeast strains containing incompatible MLH1 and PMS1 MMR alleles. Our work supports an
incompatibility model in which an elevation in mutation rate contributes to adaptation to stress conditions through
the acquisition of beneficial mutations. However, long-term fitness costs associated with an elevated mutation
rate must be eliminated by genetic suppression or buffered by mating. We will determine if signatures of
adaptation to MMR incompatibility can be directly observed in yeast populations by first screening for mutations
in PMS1 which partially or fully restore compatibility with m

## Key facts

- **NIH application ID:** 11324513
- **Project number:** 5R35GM134872-07
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Eric E. Alani
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $430,989
- **Award type:** 5
- **Project period:** 2020-01-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11324513

## Citation

> US National Institutes of Health, RePORTER application 11324513, Roles for Mismatch Repair Proteins in Maintaining Genome Stability (5R35GM134872-07). Retrieved via AI Analytics 2026-07-04 from https://api.ai-analytics.org/grant/nih/11324513. Licensed CC0.

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