# Mechanisms of RNA-dependent DNA repair in humans

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $456,390

## Abstract

Summary of the project
DNA double-strand breaks (DSB), the most harmful type of DNA lesions, are faithfully repaired by Homologous
recombination (HR). It is universally accepted that HR uses homologous dsDNA as a template for DSB repair.
However, recent studies indicate that homologous RNA can also be utilized by HR. RNA may serve as a
template for DSB repair or as a primer in the R-loop structure (three-stranded nucleic acid structure consisting
of a DNA-RNA hybrid and the displaced ssDNA strand) during restart of DNA replication stalled at DNA
lesions. Since ~75% of human genome are capable of being transcribed, RNA may play a significant role in
DNA repair. However, very little is known about the mechanisms of RNA-dependent DSB repair by HR.
 Recently, we and others found that RAD52 protein plays an important role in RNA-dependent DSB repair in
yeast and humans. We showed that RAD52 promotes formation of RNA:DNA hybrids through a novel
mechanism: inverse RNA strand exchange. In contrast to the conventional (forward) reaction that is initiated at
ssDNA to carry out DNA strand exchange with homologous dsDNA, the inverse reaction is initiated at dsDNA
containing DSB to carry out strand exchange with homologous RNA (or ssDNA).
 RAD52-promoted inverse RNA strand exchange is stimulated by Replication Protein A (RPA), a ubiquitous
ssDNA binding protein. In addition, our current data indicate that RPA may have a novel direct role in RNA-
dependent DSB repair. We found that RPA binds RNA with high affinity in vitro and forms RPA-RNA
complexes in human cells. Furthermore, our data show that RPA can promote formation of R-loops in vitro.
being the first known protein that possesses this activity.
 Using biochemical, cellular, single-molecule, and reconstitution approaches we want to understand the
mechanisms of RNA-dependent DDB repair promoted by human RAD52 and RPA and its role in genome
maintenance. Our AIMs are to study: 1) the mechanism of RAD52-promoted inverse RNA strand exchange
and its role in DNA repair and 2) the role of RPA in RNA-dependent DNA repair. The proposed studies are
expected to contribute to our understanding of the mechanisms of DNA repair in humans and will help to
identify critical functions of RAD52 and RPA in BRCA1/2-deficient tumor cells for development of new cancer
therapies.

## Key facts

- **NIH application ID:** 10347369
- **Project number:** 5R01GM136717-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** ALEXANDER V MAZIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $456,390
- **Award type:** 5
- **Project period:** 2020-04-16 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347369

## Citation

> US National Institutes of Health, RePORTER application 10347369, Mechanisms of RNA-dependent DNA repair in humans (5R01GM136717-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10347369. Licensed CC0.

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