# Elucidating Mechanisms of Recognition and Excision of Damaged Bases by NEIL glycosylases

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $280,388

## Abstract

Oxidative stress erodes the integrity of DNA by modifying DNA bases and has been linked to cancer,
neurological disorders and aging. The NEIL glycosylases initiate base excision repair of oxidized base lesions
by catalyzing the cleavage of the N-glycosidic linkage to the 2’-deoxyribose and are capable of removing a
wide array of modified DNA bases. The NEIL glycosylases are unique in acting in a variety of different
contexts beyond duplex DNA, such as ssDNA, and G-quadruplexes, that has suggested that these enzymes
play central roles in repair, replication and transcription. We have shown that hydantoin lesions, that are
formed formed under conditions of high oxidative stress, and in G-rich sequences such as G-quadruplexes, are
the best substrates for the NEIL glycosylases. Our laboratory was also the first to provide a direct link between
RNA editing and DNA repair by showing lesion processing by NEIL1 is modulated by an RNA editing reaction
that changes the codon for amino acid position 242 in the lesion recognition loop of the enzyme, switching the
residue from the genomically encoded lysine to an arginine. This change alters NEIL1 glycosylase rate
constants in a lesion and DNA context dependent manner. Lesion identity and context also influences the
extent of NEIL1 base excision, and this lesion binding property suggest roles in regulating replication and
transcription. We have also uncovered unique differences between the NEIL1 and NEIL3 in the removal of
hydantoin lesions from different G-quadruplex sequences. The presence of different G-quadruplex sequences
in gene promoters, curiously in the DNA repair enzymes themselves, suggests that the observed differences in
extents of lesion excision, and the presence of non-productive binding, may alter transcription in response to
oxidative stress. These observations further implicate NEIL enzymes in processes beyond classic BER, and
further underscore the tight interdependence of nucleic acid transactions. This project will entail using a multi-
faceted approach involving enzymology, nucleic acid chemistry, biophysical methods and cellular assays to
probe the lesion and context dependent properties of NEIL1, 2 and 3 to make direct connections between
molecular defects in particular aspects of damage recognition and base excision on preventing DNA mutations
and altering gene transcription.

## Key facts

- **NIH application ID:** 10280321
- **Project number:** 1R01GM143557-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** SHEILA Sue DAVID
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $280,388
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280321

## Citation

> US National Institutes of Health, RePORTER application 10280321, Elucidating Mechanisms of Recognition and Excision of Damaged Bases by NEIL glycosylases (1R01GM143557-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10280321. Licensed CC0.

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