PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability
Shuai Ma, Cheng Cao, Shiyou Che, Yuejiao Wang, Dongxue Su, Shuai Liu, Wenchen Gong, Ling Liu, Jixue Sun, Jiao Zhao, Qian Wang, Nan Song, Tong Ge, Qiushi Guo, Shanshan Tian, Charlie Degui Chen, Tao Zhang, Ju Wang, Xiang Ding, Fuquan Yang, Guoguang Ying, Jie Yang, Kai Zhang, Yi Zhu, Zhi Yao, Na Yang, Lei Shi
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.