# Mechanistic Dissection of the BRCA1-SETX-dependent Pathway of R-loop Avoidance and Genome Maintenance

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $470,303

## Abstract

Project Summary
Maintenance of genomic integrity depends on the ability of cells to repair damaged DNA and resolve
transcription-replication conflicts. In this regard, R-loops, three-stranded nucleic acid structures that
harbor an RNA transcript hybridized to a DNA template, can compromise genome stability in multiple
ways. Specifically, the ssDNA within the R-loop structure is vulnerable to nucleolytic cleavage, resulting
in transcription-associated mutagenesis or transcription-associated recombination. Moreover, collisions
of the DNA replication machinery with R-loops can cause replication fork collapse, DNA double-strand
breaks (DSBs), fork fusions, and chromosome translocations, which can then lead to neoplastic
transformation and tumorigenesis.
This competitive continuation of our MPI grant leverages our unique expertise in DNA repair enzymology
and cell biology modeling to delineate the structure-function of an R-loop resolution machinery comprised
of the SF1 family helicase Senataxin (SETX) and the tumor suppressor complex BRCA1-BARD1. In
Specific Aim 1, we will define the unusually versatile nucleic acid unwinding activity of SETX and test
the hypothesis that SETX resolves R loops directly through specific unwinding activity. Specific Aim 2
will determine the role of BRCA1-BARD1 in SETX-mediated R-loop resolution to test the hypothesis that
BRCA1-BARD1 cooperates with SETX to resolve pathological R-loops by interrogating SETX and
BRCA1-BARD1 in our reconstituted biochemical systems and in cells.
This MPI renewal is based on the longstanding and productive collaboration between Dr Patrick Sung, a
leading DNA repair enzymologist, and Dr Gary Kupfer, a physician-scientist who has utilized the genetic
model of Fanconi anemia to advance understanding of DNA repair pathways and mechanisms.
Together, with numerous coauthored papers of high significance, our continuing collaborative endeavors
promise to exert impact of the highest degree and to provide insight into the mechanistic underpinnings
of a major genome maintenance pathway that is linked to tumor suppression pathways.

## Key facts

- **NIH application ID:** 10876352
- **Project number:** 5R01CA168635-13
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Gary M Kupfer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $470,303
- **Award type:** 5
- **Project period:** 2013-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876352

## Citation

> US National Institutes of Health, RePORTER application 10876352, Mechanistic Dissection of the BRCA1-SETX-dependent Pathway of R-loop Avoidance and Genome Maintenance (5R01CA168635-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876352. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*