ArticleScience advances2021
PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.
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Article in Science advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15citing papers in PubMed
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Development of a structurally distinct TopBP1 inhibitor that enhances PARP blockade and reverses osimertinib resistance.Science advances · 2026Article
- KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage.bioRxiv : the preprint server for biology · 2026Article
- Evaluating the Diagnostic Value and Molecular Mechanism of Energy Metabolism-Related Gene PEA15 in Sepsis.Journal of inflammation research · 2026Article
- Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention.Molecular cancer · 2025Review
- Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast tumor models.The Journal of clinical investigation · 2025Article
- Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair.Science advances · 2025Article
- Discovery and structural studies of histone demethylases.Frontiers in epigenetics and epigenomics · 2025Review
- Article
- PHF8/KDM7B: A Versatile Histone Demethylase and Epigenetic Modifier in Nervous System Disease and Cancers.Epigenomes · 2024Review
- Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex.ACS omega · 2024Article
- Gross Chromosomal Rearrangement at Centromeres.Biomolecules · 2023Review
- Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons.Nature communications · 2023Article
- Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy.Cell death and differentiation · 2022Article
- LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin.Genome biology · 2022Article
- Phosphorylation-dependent assembly of DNA damage response systems and the central roles of TOPBP1.DNA repair · 2021Review
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Authors and funding
27 authors at 4 institutions in 1 country.
Shuai MaState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0001-6416-642X
Cheng CaoState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-3960-1183
Shiyou CheState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Medical Data Analysis and Statistical Research of Tianjin, Nankai University, 300353 Tianjin, China.ORCID 0000-0001-7238-5622
Yuejiao WangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0001-9759-3743
Dongxue SuState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.ORCID 0000-0002-6018-0694
Shuai LiuState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-3593-2532
Wenchen GongState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.
Ling LiuState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-6513-7732
Jixue SunState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Medical Data Analysis and Statistical Research of Tianjin, Nankai University, 300353 Tianjin, China.
Jiao ZhaoState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0003-0076-7896
Qian WangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0003-0008-8367
Nan SongState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0003-2513-0461
Tong GeState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0001-5628-6325
Qiushi GuoState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0003-4514-9469
Shanshan TianState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-8670-6375
Charlie Degui ChenState Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Tao ZhangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-0694-5916
Ju WangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.
Xiang DingLaboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.ORCID 0000-0003-1097-176X
Fuquan YangLaboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.ORCID 0000-0002-2841-5342
Guoguang YingState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.
Jie YangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0002-5301-7610
Kai ZhangState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0003-2800-0531
Yi ZhuState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.ORCID 0000-0001-7725-9166
Zhi YaoState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China. shilei@tmu.edu.cn yangnanku@nankai.edu.cn yaozhi@tmu.edu.cn.ORCID 0000-0001-8472-0731
Na YangState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Medical Data Analysis and Statistical Research of Tianjin, Nankai University, 300353 Tianjin, China. shilei@tmu.edu.cn yangnanku@nankai.edu.cn yaozhi@tmu.edu.cn.ORCID 0000-0002-6956-6630
Lei ShiState Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China. shilei@tmu.edu.cn yangnanku@nankai.edu.cn yaozhi@tmu.edu.cn.ORCID 0000-0003-1679-3618
Tianjin Medical University General Hospital · CNChinese Academy of Sciences · CNNankai University · CNXiamen University · CN
Funding
No grant is acknowledged in the PubMed record.
Abstract
The checkpoint kinase ATR [ATM (ataxia-telangiectasia mutated) and rad3-related] is a master regulator of DNA damage response. Yet, how ATR activity is regulated remains to be investigated. We report here that histone demethylase PHF8 (plant homeodomain finger protein 8) plays a key role in ATR activation and replication stress response. Mechanistically, PHF8 interacts with and demethylates TOPBP1 (DNA topoisomerase 2-binding protein 1), an essential allosteric activator of ATR, under unperturbed conditions, but replication stress results in PHF8 phosphorylation and dissociation from TOPBP1. Consequently, hypomethylated TOPBP1 facilitates RAD9 (RADiation sensitive 9) binding and chromatin loading of the TOPBP1-RAD9 complex to fully activate ATR and thus safeguard the genome and protect cells against replication stress. Our study uncovers a demethylation and phosphorylation code that controls the assembly of TOPBP1-scaffolded protein complex, and provides molecular insight into non-histone methylation switch in ATR activation.
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