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PHRF1介导的TopBP1单泛素化增强了ATR激活和基因组稳定性。

Mono-ubiquitination of TopBP1 by PHRF1 enhances ATR activation and genomic stability.

作者信息

Zhao Fei, Cai Chenghui, Gao Huanyao, Moon Jaeyoung, Christyani Grania, Qin Sisi, Hao Yalan, Liu Tongzheng, Lou Zhenkun, Kim Wootae

机构信息

College of Biology, Hunan University, Changsha 410082, China.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States.

出版信息

Nucleic Acids Res. 2025 Feb 27;53(5). doi: 10.1093/nar/gkaf073.

DOI:10.1093/nar/gkaf073
PMID:40052822
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11886831/
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.

摘要

在DNA复制应激期间，TopBP1-ATR轴对于维持基因组稳定性至关重要，但TopBP1在复制应激反应中的精确调控仍知之甚少。在本研究中，我们通过与TopBP1相互作用，鉴定出PHD和泛素连接酶结构域1（PHRF1）是一种重要的ATR激活因子。我们的分析揭示了癌症患者中PHRF1与基因组稳定性之间的相关性。从机制上讲，PHRF1以依赖其PHD结构域和组蛋白甲基化的方式被招募到DNA损伤处。随后，PHRF1在赖氨酸73处单泛素化TopBP1，这增强了TopBP1-ATR相互作用并激活ATR。PHRF1的缺失会破坏ATR激活并使细胞对复制应激诱导剂敏感。此外，小鼠中Phrf1的条件性敲除导致早期致死率和ATR-Chk1轴信号传导受损。总的来说，我们的研究结果确立了PHRF1作为TopBP1的新型E3连接酶，通过增强TopBP1-ATR信号传导来协调复制应激反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/379b7a61db2e/gkaf073fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/318e6ae08916/gkaf073figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/897b7673c4dd/gkaf073fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/730eec58ae94/gkaf073fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/6782978d60da/gkaf073fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/d7c636c2fd64/gkaf073fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/b5efc12b1903/gkaf073fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/964cf144ad36/gkaf073fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/379b7a61db2e/gkaf073fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/318e6ae08916/gkaf073figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/897b7673c4dd/gkaf073fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/730eec58ae94/gkaf073fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/6782978d60da/gkaf073fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/d7c636c2fd64/gkaf073fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/b5efc12b1903/gkaf073fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/964cf144ad36/gkaf073fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e084/11886831/379b7a61db2e/gkaf073fig7.jpg

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本文引用的文献

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USP13 regulates the replication stress response by deubiquitinating TopBP1.USP13 通过去泛素化 TopBP1 调节复制应激反应。
DNA Repair (Amst). 2021 Apr;100:103063. doi: 10.1016/j.dnarep.2021.103063. Epub 2021 Feb 6.
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TopBP1 assembles nuclear condensates to switch on ATR signaling.
TopBP1 组装核凝聚物以开启 ATR 信号。
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