# Investigating DNA double-strand break repair mechanisms in mammalian cells

> **NIH NIH R35** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $443,750

## Abstract

Principal Investigator: Wu, Xiaohua
Project Summary
 Gross chromosomal rearrangement (GCR) is a hallmark of cancer cells and the
cause of structural variant formation in genetic disorders. DNA double-strand breaks (DSBs)
are a major source to induce GCR, but the details on how the DSB repair process leads to
genome instability in cancers and other genetic disorders remains elusive.
 Microhomologies are prevalent at chromosomal break junctions in cancer and other
human diseases, suggesting that microhomology-mediated end joining (MMEJ) is one major
player to mediate GCRs. Repetitive sequences are abundant, constituting about half of the
human genome, which raises the question of how recombination between repetitive
sequences is suppressed to prevent genome instability. In this proposal, we aim to
investigate the mechanisms underlying MMEJ and repeat-mediated recombination in
mammalian cells.
 We have established multiple EGFP-based DSB repair reporter systems, which
enable us to study different DSB repair pathways in mammalian cells. By using newly
established MMEJ reporters, we identified new players in the MMEJ pathway. We will
investigate how these MMEJ players regulate MMEJ to balance its usage and its mutagenic
consequences. We will also study the biological role of MMEJ in repairing replication-
associated DSBs and in coping with replication and oncogenic stress, and address how
MMEJ contributes to genome instability and the oncogenic process. Additionally, we will
determine the mechanisms of repeat-mediated recombination in causing deletions and
translocations, and study the role of heteroduplex rejection in preventing recombination
among divergent repeats. These studies will generate much-needed new knowledge to fill
the gap in our understanding of DSB repair mechanisms and the cause of genome
instability that is associated with the oncogenic process and other genetic disorders.

## Key facts

- **NIH application ID:** 10380899
- **Project number:** 5R35GM141868-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Xiaohua Wu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $443,750
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380899

## Citation

> US National Institutes of Health, RePORTER application 10380899, Investigating DNA double-strand break repair mechanisms in mammalian cells (5R35GM141868-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380899. Licensed CC0.

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