# 53BP1-dependent pathway in DNA repair

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

PROJECT SUMMARY
 Despite rapid progress in defining distinct DNA repair pathways over the past few years, our knowledge of
p53-binding protein 1 (53BP1) in DNA repair remains incomplete. My laboratory is interested in elucidating the
molecular mechanisms underlying genomic instability and tumorigenesis. Since I started my laboratory in
1999, we have discovered and characterized many essential DNA damage checkpoint and repair proteins. Our
long-term goal is to reveal the complex regulation of the DNA repair network, which will permit us to
meaningfully contribute to cancer biology and treatment.
 This proposal focuses on 53BP1, a key component in DNA repair. Many years ago, our group was one of
the first to demonstrate the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout
mice and revealed that 53BP1 is required for DNA repair and acts as a tumor suppressor in vivo. In addition,
we elucidated the regulation of 53BP1 after DNA damage. In particular, over the past decade, we and others
demonstrated that the H2AX-dependent DNA damage signaling pathway, composed of H2AX, MDC1, RNF8,
and RNF168, controls the recruitment and accumulation of 53BP1 at sites of DNA breaks. In particular, we
showed that 53BP1, because of its role in DNA repair, is critical for a particular repair process called class-
switch recombination, indicating that 53BP1 is involved in a special DNA repair pathway that is distinctly
different from the canonical nonhomologous end-joining (NHEJ) pathway. Moreover, our recent studies and
those of others suggest that 53BP1 controls two downstream sub-pathways and suppresses homologous
recombination (HR) repair in BRCA1-deficient cells, which is critically important for response to cancer
therapies based on poly (ADP-ribose) polymerase inhibitors (PARPi). Together, these data highlight the
existence of a bona fide 53BP1-dependent repair pathway that has not been thoroughly investigated. Our
goals in this proposal are to further understand the 53BP1-dependent repair pathway and reveal
mechanistically how it counteracts the HR repair pathway in response to DNA damage.
 To achieve these goals, we propose the following specific aims: 1) delineate the 53BP1-dependent end-
joining repair pathway; 2) elucidate the molecular mechanisms underlying the regulation and function of the
RIF1-REV7 branch of the 53BP1-dependent repair pathway; and 3) reveal mechanistically how the HR
pathway operates in the absence of BRCA1 and 53BP1. These proposed studies are significant because they
not only will elucidate the 53BP1-dependent repair pathway in the complex DNA repair network, but also will
provide ways to overcome therapy resistance for cancer patients.

## Key facts

- **NIH application ID:** 9937675
- **Project number:** 5R01CA216437-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Junjie Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-06-14 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937675

## Citation

> US National Institutes of Health, RePORTER application 9937675, 53BP1-dependent pathway in DNA repair (5R01CA216437-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937675. Licensed CC0.

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