# Mismatch Repair and Carcinogenesis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $362,792

## Abstract

MISMATCH REPAIR AND CARCINOGENESIS
PROJECT SUMMARY / ABSTRACT
Defects in human mismatch repair (MMR) are the cause of Lynch syndrome aka hereditary non-polyposis
colorectal cancer (LS/HNPCC), as well as 10-40% of various sporadic cancers. MMR corrects DNA polymerase
misincorporation errors, suppresses recombination between non-allelic partially homologous DNA sequences,
and functions as a lesion sensor in DNA damage signaling. The unrepaired errors in MMR-deficient cells lead
to increased genomic mutations that drives tumorigenesis, while the lack of damage sensing results in resistance
to several common chemotherapeutics. Conversely, MMR defective tumors appear to activate cellular innate
immunity that results in strikingly effective PD1/PD-L1-based immunotherapy. Despite decades of study, critical
aspects of MMR mechanics remain uncertain, the sequence of events that leads to MMR damage signaling is
poorly understood, and the mechanism that connects MMR to innate immunity is largely a mystery.
Four MMR genes account for most of the LS/HNPCC mutations and include the highly conserved MutS homologs
(MSH) and MutL homologs (MLH/PMS) MSH2, MSH6, MLH1 and PMS2. During the last funding period, we
expanded our single molecule imaging capabilities and discovered that the MSH and MLH/PMS proteins interact
to form novel cascading sliding clamps on a mismatched DNA. Once loaded by an MSH, the MLH/PMS sliding
clamps assist in detecting the error-containing strand and function as a processivity factor for MMR excision
activities, while retaining a large enough “donut hole” to transit nucleosomes. The remarkable stability and DNA
diffusion properties of the MSH and MLH/PMS sliding clamps clarified our understanding of MMR mechanisms,
while provoking new concepts for strand-specific excision and damage signaling. Remarkably, the MSH and
MLH/PMS sliding clamps displayed entirely random motions when on the DNA. Deterministic mechanisms have
historically underpinned MMR models, where static complexes and well-defined stepwise biochemical
sequences are proposed to complete repair events. This renewal application will explore the hypothesis that the
entire multi-component multi-pathway MMR process is Stochastic: governed by chance encounters, varied
repair intermediates and/or MMR component exchanges that are orchestrated and anchored to the DNA by
dynamic MSH and MLH/PMS sliding clamps. Understanding the depth of biochemical randomness during MMR
will facilitate similar biophysical studies of more complex DNA repair systems.
We propose the following Specific Aims: 1) examine the interactions and competition between human MMR
components in real-time, 2) detail the dynamic selection and interchange between strand-specific excision
components during MMR, 3) examine fundamental damage recognition and signaling interactions on chromatin
substrates, and 4) visualize human MMR component interactions with single molecule resolution in vivo. The
overall goal of this resea...

## Key facts

- **NIH application ID:** 10874616
- **Project number:** 5R01CA067007-29
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Richard Fishel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,792
- **Award type:** 5
- **Project period:** 1995-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874616

## Citation

> US National Institutes of Health, RePORTER application 10874616, Mismatch Repair and Carcinogenesis (5R01CA067007-29). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10874616. Licensed CC0.

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