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.
[1]Tianjin Med Univ, Tianjin Med Univ Canc Inst & Hosp,Key Lab Immune, Gen Hosp,Minist Educ,Key Lab Breast Canc Prevent, State Key Lab Expt Hematol,Collaborat Innovat Ctr, Tianjin 300070, Peoples R China.
[2]Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Tianjin 300353, Peoples R China.
[3]Nankai Univ, Key Lab Med Data Anal & Stat Res Tianjin, Tianjin 300353, Peoples R China.
[4]Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China.
[5]Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, State Key Lab Mol Biol,Shanghai Key Lab Mol Andro, Shanghai 200031, Peoples R China.
[6]Chinese Acad Sci, Inst Biophys, Lab Prote, Beijing 100101, Peoples R China.
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