# Novel regulations of DNA damage repair

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $436,368

## Abstract

PROJECT SUMMARY
 Defects in DNA damage response and DNA repair are the driving forces of genomic instability and
tumorigenesis. Gaining a better understanding of the pathways involved in DNA repair not only increases our
understanding of cancer etiology, but also provides new targets for cancer therapies. A key protein involved in
DNA repair and tumorigenesis is p53-binding protein 1, i.e. 53BP1.
 My laboratory has been working on 53BP1 for many years. Our group was one of the first to demonstrate
the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout (KO) mice; we also
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. We and others demonstrated that the H2AX-dependent
DNA damage signaling pathway controls the recruitment and accumulation of 53BP1 at sites of DNA breaks.
However, 53BP1 can also localize to DNA damage sites in an H2AX-independent manner, although the
underlying mechanisms remain to be determined. Moreover, we showed that 53BP1 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 pathway. Our recent studies
and those of others suggest that 53BP1 suppresses homologous recombination repair in BRCA1-deficient
cells, which is critically important for response to poly (ADP-ribose) polymerase inhibitor-based cancer
therapies. Together, these data highlight the importance of 53BP1 in counteracting homologous recombination
repair in response to DNA damage. In this proposal, we plan to focus on 53BP1 and elucidate at the molecular
level how 53BP1 is regulated after DNA damage and contributes to DNA repair and genome maintenance.
 To further understand the regulation of 53BP1 localization and function at DNA damage sites, we recently
performed tandem affinity purification coupled with mass spectrometry analysis to identify proteins that would
specifically associate with a region of 53BP1, which is necessary and sufficient for its localization to DNA
damage sites. Surprisingly, we uncovered several novel 53BP1-binding proteins, including NUDT16,
NUDT16L1, and DEK. In this proposal, we will 1) further determine the roles of NUDT16L1 and NUDT16 in
53BP1 regulation and in the DNA damage response, and 2) elucidate the functional significance of DEK and
other newly discovered 53BP1-associated proteins in damage-induced 53BP1 localization, DNA repair, and
the maintenance of genomic integrity. These studies will help us understand the key components that act
upstream of 53BP1 and function together with 53BP1 in DNA repair and genome maintenance.

## Key facts

- **NIH application ID:** 10087898
- **Project number:** 5R01CA216911-05
- **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:** 2021
- **Award amount:** $436,368
- **Award type:** 5
- **Project period:** 2017-03-16 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087898

## Citation

> US National Institutes of Health, RePORTER application 10087898, Novel regulations of DNA damage repair (5R01CA216911-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10087898. Licensed CC0.

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