# Mismatch Repair and Carcinogenesis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $374,292

## Abstract

MISMATCH REPAIR AND CARCINOGENESIS
PROJECT SUMMARY / ABSTRACT
Defects in the human mismatch repair (MMR) genes are the cause of Lynch syndrome (LS/HNPCC), as well
as 10-40% of sporadic colorectal, gastric, endometrial, ovarian and upper urinary tract tumors. MMR
recognizes and repairs polymerase misincorporation errors, suppresses recombination between non-allelic
partially homologous DNA sequences, and functions as a lesion sensor in DNA damage signaling. Unrepaired
errors in MMR-deficient cells lead to increased mutations (Mutator Phenotype) that drive tumorigenesis and
MMR-deficient tumors are resistant to several common cancer chemotherapeutic drugs.
MMR is a bidirectional excision-resynthesis process that is initiated at a distant DNA strand break, which may
be located 3' or 5' and hundreds to thousands of nucleotides from the mismatch. The fidelity of post-replication
MMR depends on communicating mismatch recognition to the distant strand break and then exclusively
directing excision to the DNA strand containing the misincorporation error. Resynthesis of the resulting DNA
gap is independent from MMR-directed excision and performed by the replicative polymerase.
How MMR components coordinate mismatch or lesion recognition with the numerous downstream activities
that perform DNA excision or damage signaling remains uncertain. In the last 5-year period of support we
developed unique real-time single molecule imaging methods that visualized fundamental protein functions and
detailed the ensemble 5'-MMR excision process. The most intriguing observation was that every step of MMR
appeared stochastic. Dynamic often non-productive MMR complexes undergoing thermal (Brownian) motion
on the mismatched DNA were continuously formed and dissolved during the excision process. While these
superficially random progressions showcased the chaotic nature of biology, it was apparent that sufficient
productive events occurred to faithfully complete MMR in most cases. In this renewal application we propose
to detail how these dynamic processes are coordinated in vitro and in vivo to clearly determine the mechanism
of MMR. It is our hypothesis that many of the several hundred LS/HNPCC missense mutations affect poorly
understood stochastic steps in MMR and DNA damage signaling.
We will accomplish the following Specific Aims: 1.) visualize the complete ensemble human 3'- and 5'-MMR
process in vitro in single molecule detail, 2.) examine the dynamic interactions between defined physiologically
relevant chromatin and human MMR, and 3.) examine human MMR component interactions with single
molecule detail in vivo. The goal of this proposal is to visualize and quantify the MMR progressions that
ultimately lead to cancer and therapeutic drug resistance.

## Key facts

- **NIH application ID:** 10129904
- **Project number:** 5R01CA067007-26
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Richard Fishel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,292
- **Award type:** 5
- **Project period:** 1995-04-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129904

## Citation

> US National Institutes of Health, RePORTER application 10129904, Mismatch Repair and Carcinogenesis (5R01CA067007-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10129904. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*