# Study of Break-induced Replication in Mammalian Cells

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $478,803

## Abstract

Gross chromosomal rearrangement (GCR) is a hallmark of cancer and DNA double-
strand breaks (DSBs) constitute a major source of GCR. Many GCR events involve a
replicative process, but the underlying mechanism is not clear. Based on the study in yeast,
a DSB repair pathway called break-induced replication (BIR) is believed to be a major
source of replicative GCR. Since the mechanistic study of BIR has been mostly carried out
in yeast, a model system to study BIR mechanism and its role in suppressing genome
instability in mammalian cells is highly in demand.
 We have established a novel EGFP-based BIR reporter, making it possible to
systematically study BIR mechanisms and analyze its genetic components in mammalian
cells. We hypothesize that BIR, on one hand, is involved in DSB repair to prevent
chromosome breakages and help maintenance of genome stability, but on the other hand,
is highly mutagenic and its dysregulation would contribute to genome instability. In this
proposal, we will study how BIR is induced by replication and oncogenic stress and
contributes to genome instability. We will also study the role and the underlying mechanism
of replication helicases such as Pif1 and other replication proteins in BIR. We will decipher
the role of ATR-mediated phosphorylation in promoting BIR and examine functional
interplay of replication proteins with Rad51 at collapsed forks to initiate BIR for replication
restart. Our study will shed light on how BIR is operated in mammalian cells and provide
new mechanistic insight on the maintenance of genome integrity. It will also open new
opportunities to explore the BIR pathway for cancer treatment.

## Key facts

- **NIH application ID:** 10756440
- **Project number:** 5R01CA244912-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Xiaohua Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $478,803
- **Award type:** 5
- **Project period:** 2019-12-10 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756440

## Citation

> US National Institutes of Health, RePORTER application 10756440, Study of Break-induced Replication in Mammalian Cells (5R01CA244912-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10756440. Licensed CC0.

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