# Elucidating control of BRCA1 by SIRT2 in DNA double-strand break repair

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $4,500

## Abstract

PROJECT SUMMARY
DNA Damage Response (DDR) pathways, including DNA repair and cell-cycle checkpoints, are critical for
protecting against genomic insults and thus for maintaining genome integrity. The most deleterious type of
DNA damage is the DNA double-strand break (DSB), and deficiencies in the DDR DSB subset repair pathways
result in genomic instability via chromosomal aberrations and mutations, which can ultimately lead to an
increased risk for disease, including cancer. However, the mechanisms regulating DSB repair pathways have
yet to be fully elucidated, leaving us with an incomplete understanding of how dysregulation or mutation of
proteins involved in DSB repair pathways increases the risk for developing cancer. Our lab has recently
identified Sirtuin 2 (SIRT2), a deacetylase and known murine tumor suppressor, as a novel regulator of the
DDR. SIRT2-deficient cells are hypersensitive to DNA damage and show impaired checkpoint responses
following ionizing radiation. Preliminary data indicate that SIRT2 is necessary for the proper repair of DSBs
through the homologous recombination (HR) repair pathway and is a novel regulator of Breast Cancer 1
(BRCA1), a tumor suppressor and critical regulator of HR. Our findings suggest that SIRT2 is an important
player in the regulation of DSB repair and may contribute to the development of cancers that arise from faulty
DSB repair pathways. However, the precise mechanism that SIRT2 plays in the repair of DSBs remains
unclear. In this project, a combination of genetic, biochemical, molecular biological, and cell biological
approaches will be used to test the hypothesis that
least in part, by promoting BRCA1 function in HR repair through deacetylation. The specific aims of this
research proposal are 1) to determine the functional significance of the SIRT2/BRCA1 interaction during HR
repair and 2) to determine the sites of SIRT2 deacetylation on BRCA1 in response to DNA damage and their
functional significance. Insights gained from completion of this work will contribute to our fundamental
knowledge of DSB repair pathways and how dysregulation of DSB repair by the SIRT2 and BRCA1 tumor
suppressor proteins leads to genomic instability and an increased risk for cancer. Additionally, these findings
will provide invaluable insights into how to exploit the interplay between SIRT2 and BRCA1 as a novel
therapeutic approach for the prevention and treatment of cancer.
SIRT2 maintains genome integrity in response to DSBs, at

## Key facts

- **NIH application ID:** 9964707
- **Project number:** 5F31CA225124-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Elizabeth Minten
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $4,500
- **Award type:** 5
- **Project period:** 2018-07-12 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964707

## Citation

> US National Institutes of Health, RePORTER application 9964707, Elucidating control of BRCA1 by SIRT2 in DNA double-strand break repair (5F31CA225124-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964707. Licensed CC0.

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