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Nucleic Acids Res., Volume 53, Issue 5, 24 March 2025, gkaf073 | https://doi.org/10.1093/nar/gkaf073
Mono-ubiquitination of TopBP1 by PHRF1 enhances ATR activation and genomic stability
Fei Zhao1, Chenghui Cai1, Huanyao Gao2, Jaeyoung Moon3, Grania Christyani3, Sisi Qin3, Yalan Hao4, Tongzheng Liu5, Zhenkun Lou 2,*, Wootae Kim 3,*
1College of Biology, Hunan University, Changsha 410082, China
2Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States
3Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan 31151 Chungcheongnam-do, Republic of Korea
4Analytical Instrumentation Center, Hunan University, Changsha 410082, China
5College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 510632, China
*To whom correspondence should be addressed. : Wootae Kim
Correspondence may also be addressed to Zhenkun Lou.
1College of Biology, Hunan University, Changsha 410082, China
2Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States
3Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan 31151 Chungcheongnam-do, Republic of Korea
4Analytical Instrumentation Center, Hunan University, Changsha 410082, China
5College of Pharmacy/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 510632, China
*To whom correspondence should be addressed. : Wootae Kim
Correspondence may also be addressed to Zhenkun Lou.
Abstract
The TopBP1-ATR axis is critical for maintaining genomic stability during DNA replication stress, yet the precise regulation of TopBP1 in replication stress responses remains poorly understood. In this study, we identified PHD and Ring Finger Domains 1 (PHRF1) as an important ATR activator through its interaction with TopBP1. Our analysis revealed a correlation between PHRF1 and genomic stability in cancer patients. Mechanistically, PHRF1 is recruited to DNA lesions in a manner dependent on its PHD domain and histone methylation. Subsequently, PHRF1 mono-ubiquitinates TopBP1 at lysine 73, which enhances the TopBP1-ATR interaction and activates ATR. Depletion of PHRF1 disrupts ATR activation and sensitizes cells to replication stress-inducing agents. Furthermore, conditional knockout of Phrf1 in mice leads to early lethality and impaired ATR-Chk1 axis signaling. Collectively, our findings establish PHRF1 as a novel E3 ligase for TopBP1, coordinating the replication stress response by enhancing TopBP1-ATR signaling.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-10)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
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