# DNA Damage Repair by MUTYH and MUTYH Variants Associated with Colorectal Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $284,869

## Abstract

MUTYH-associated polyposis (MAP) is an inherited colorectal cancer (CRC) syndrome that results from
inherited biallelic mutations in the gene for the MUTYH base excision repair (BER) glycosylase. Our laboratory
provided enzymatic analysis on the functional defects of two missense variants of MUTYH found in colorectal
cancer that was key for establishing the connection between MUTYH variants and colorectal cancer. MUTYH
prevents mutations associated with 8-oxo-7,8-dihydro-2’-deoxyguanosine (OG) by removal of misincorporated
adenine residues from OG:A mismatches, and thus aberrantly functioning MUTYH leads to the accumulation of
mutations in tumor suppressor genes. Since the original discovery of MAP over 300 different mutations have
been reported in MUTYH. This project is focused on revealing fundamental features of MUTYH and MUTYH
variants. Our underlying hypothesis is that a detailed molecular understanding of OG:A mismatch recognition
goes hand-in-hand with revealing intricacies of the relationship between MUTYH and cancer. By corrrelating
results from enzymatic assays with cellular assays in E. coli and mammalian cells we have uncovered the
impact of specific molecular defects in damage recognition and base excision on overall MUTYH-mediated
repair. This has led to uncovering many new surprising features of MUTYH-mediated repair that will be the
focus of this renewal grant application. Specifically, we will use a multi-faceted approach involving nucleic acid
chemistry, enzymology, single-molecule experiments and cellular assays to analyze a large number of MUTYH
variants localized near the two metal cofactors and FSH OG recognition motif to reveal insight into critical
features impacting damage recognition and repair. We also will evaluate the impact of MUTYH variants in the
context of chromatin. We will also evaluate how damage recognition by MUTYH in chromatin may be
facilitated by the damage sensor UV-DDB. We recently showed that MUTYH binding to abasic sites in DNA
mediates a cytotoxic response to alkylation damage. We will determine if the interaction of MUTYH with
abasic sites is the underlying origin of the growing implication of MUTYH involvement in the response to DNA
damage beyond OG:A mispairs, such as UV light and chemotherapeutic DNA damaging agents. The
significance of this work is that it will provide important information into the mechanisms by which MUTYH
dysfunction, either inherited or acquired, sets the stage for carcinogenesis and this information will directly
influence appropriate patient management. In addition, the role of MUTYH and MUTYH variants in mediating
celllular responses to oxidative damage, alkylation and UV light may provide the basis for innovative new
therapeutic approaches.

## Key facts

- **NIH application ID:** 10653071
- **Project number:** 5R01CA067985-27
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** SHEILA Sue DAVID
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $284,869
- **Award type:** 5
- **Project period:** 1995-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653071

## Citation

> US National Institutes of Health, RePORTER application 10653071, DNA Damage Repair by MUTYH and MUTYH Variants Associated with Colorectal Cancer (5R01CA067985-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10653071. Licensed CC0.

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