# DNA Adduct-Induced Mutagenesis

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $524,554

## Abstract

Project Summary:
Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide. Its etiology is complex, including
infection by hepatitis B virus (HBV) and chronic dietary exposures to the mycotoxin aflatoxin B1 (AFB1).
Genomic analyses of AFB1-associated human HCC reveal specific mutational signatures, e.g., "Signature 24".
Recently, John Essigmann, Lawrence Loeb, and co-workers used a mouse model of HCC tumorigenesis to
show that a unique mutational spectrum appearing early after AFB1 exposure persists until tumors develop
over a year later. It recapitulates important aspects of the human "Signature 24" spectrum. In pre-neoplastic
murine hepatocytes, 25% of the spectrum consists of G→T transversions in the sequence 5'-CGC-3', which
also possesses epigenetic significance due to the potential for cytosine methylation. We seek to understand
the chemistry and biology driving mutation signatures associated with exposures to AFB1. AFB1 adducts in
DNA rearrange to AFB1-formamidopyrimidine (AFB1-FAPY) adducts, which are genotoxic, yielding primarily G
to T transversions. AFB1-FAPY exists as a mixture of configurational and conformational isomers. We recently
showed that the human Base Excision Repair (BER) glycosylase NEIL1 plays a key role in removing AFB1-
FAPY damage from DNA—humans deficient in NEIL1 may be at risk for AFB1-induced HCCs. This competing
continuation application is premised upon the need to evaluate how NEIL1-initiated BER and error-prone
bypass of AFB1-FAPY adducts is modulated by adduct isomeric equilibria and cytosine methylation status. The
fundamental hypothesis is that responses to AFB1-FAPY damage depend upon sequence-specific differences
in this mixture. If the aims of this application are successful, we will obtain sequence-specific structure-activity
relationships for AFB1-FAPY isomeric adducts, with respect to DNA base excision repair (BER) and error-
prone replication, which may act as drivers for unique AFB1-based mutational signatures observed in HCC.
Additionally, our work may identify new targets for chemotherapeutic intervention in HCC.
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## Key facts

- **NIH application ID:** 10133072
- **Project number:** 5R01ES029357-28
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Michael P Stone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $524,554
- **Award type:** 5
- **Project period:** 1992-02-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133072

## Citation

> US National Institutes of Health, RePORTER application 10133072, DNA Adduct-Induced Mutagenesis (5R01ES029357-28). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133072. Licensed CC0.

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