# Function of HMCES in abasic site repair and tolerance

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $529,884

## Abstract

PROJECT SUMMARY
Thousands of abasic sites form daily in each of our cells. Many types of environmental toxins that cause
alkylation or oxidation of DNA bases to form N7-guanine adducts and 8-oxoguanine induce abasic sites.
For example, N-nitrosamines that are found in foods, detergents, solvents, plastics, and agricultural
chemicals as well as chemicals like carbon tetracholoride, potassium bromate, and chloroform that induce
oxidative stress all increase the frequency of abasic sites in DNA. Failures in managing this ubiquitous form
of DNA damage can cause a variety of diseases including cancer. The known mechanisms of repair require
an intact DNA duplex; however, abasic sites form more readily in single-stranded DNA where they are
impediments to replicative polymerases. We recently discovered a new pathway that detects and process
abasic sites in single-stranded DNA. This pathway utilizes HMCES (hydroxyl-methyl cytosine embryonic
cell specific) to detect and shield these abasic sites from deleterious processing. HMCES contains an
evolutionarily conserved domain (SRAP) that binds DNA and forms a covalent crosslink to abasic sites.
This DNA-protein crosslink prevents endonucleases from cleaving the single-stranded DNA, thereby
preventing double-strand breaks. In this proposal we will further characterize how this pathway acts to
maintain genome stability, and more broadly define how abasic sites are tolerated and repaired in the
context of DNA replication. We will utilize state of the art biochemical, genetic, and structural approaches in
human cells and cell extracts. Completing these studies will provide a mechanistic understanding of how
cells cope with a ubiquitous form of DNA damage generated by important environmental genotoxins.

## Key facts

- **NIH application ID:** 10979274
- **Project number:** 2R01ES030575-06A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** David K Cortez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $529,884
- **Award type:** 2
- **Project period:** 2019-04-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979274

## Citation

> US National Institutes of Health, RePORTER application 10979274, Function of HMCES in abasic site repair and tolerance (2R01ES030575-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979274. Licensed CC0.

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