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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.<\/jats:p>","DOI":"10.1093\/nar\/gkaf073","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T12:06:43Z","timestamp":1741349203000},"source":"Crossref","is-referenced-by-count":1,"title":["Mono-ubiquitination of TopBP1 by PHRF1 enhances ATR activation and genomic stability"],"prefix":"10.1093","volume":"53","author":[{"given":"Fei","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Biology, Hunan University , Changsha 410082 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghui","family":"Cai","sequence":"additional","affiliation":[{"name":"College of Biology, Hunan University , Changsha 410082 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