# Determining the role of RNA abasic sites in gene regulation

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $125,672

## Abstract

RNA abasic sites are recently identified modifications in RNA that are generated by
methylpurine glycosylase to regulate gene expression. They are abundant in RNA and they
stabilize RNA yet we do not know much about how they form, their precursors, and their
functions.
DNA abasic sites were identified in the 1960s and those discoveries led to the elucidation of the
base excision repair pathway in DNA damage. But RNA abasic sites were largely unknown,
except those generated by the plant poison, ricin, in ribosomal RNA. While studying proteins
that bind to the nucleic acid structure, R-loop, we identified RNA modification enzymes and
methylpurine glycosylase as well as apurinic/apyrimidinic endonuclease I that were known to
process DNA abasic sites.
We have now shown that methylpurine glycosylase cleaves the glycosidic bond in RNA to form
abasic sites and these reactions occur on RNA in RNA/DNA hybrids of R-loops. By mass
spectrometry, we found that RNA abasic sites are rather abundant, there are tens to hundreds
of thousands of them in each cell. We also found in an enhancer RNA of APOE, N6-
methyladenosines are cleaved by methylpurine glycosylase to form RNA abasic sites on R-
loops. The abasic sites then stabilize R-loops and pause RNA Polymerase II transcription. We
show that this mechanism keeps the noncoding RNA poised to activate APOE expression in
response to cellular demands.
Given that we have early evidence for the role of RNA abasic sites in the regulation of
noncoding RNA, it is necessary to better understand them. We propose to 1) examine the
genome-wide effect of nucleic-acid-mediated pausing on noncoding RNA, 2) identify other
glycosylases that form RNA abasic sites, and 3) determine what other modified RNA bases are
precursors of RNA abasic sites. Together, these results will characterize RNA abasic sites by
finding how they form and what they do.

## Key facts

- **NIH application ID:** 11010443
- **Project number:** 3R21ES034919-02S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Vivian G Cheung
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,672
- **Award type:** 3
- **Project period:** 2023-08-15 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11010443

## Citation

> US National Institutes of Health, RePORTER application 11010443, Determining the role of RNA abasic sites in gene regulation (3R21ES034919-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11010443. Licensed CC0.

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