7CMZ

Crystal Structure of BRCT7/8 in Complex with the APS Motif of PHF8

Summary for 7CMZ

• Entry DOI: 10.2210/pdb7cmz/pdb
• Descriptor: DNA topoisomerase 2-binding protein 1, Histone lysine demethylase PHF8, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: topbp1, protein binding-hydrolase complex, protein binding/hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28544.43

Authors

Che, S.Y.,Ma, S.,Cao, C.,Yao, Z.,Shi, L.,Yang, N. (deposition date: 2020-07-29, release date: 2021-03-17, Last modification date: 2024-10-30)

Primary citation

Ma, S.,Cao, C.,Che, S.,Wang, Y.,Su, D.,Liu, S.,Gong, W.,Liu, L.,Sun, J.,Zhao, J.,Wang, Q.,Song, N.,Ge, T.,Guo, Q.,Tian, S.,Chen, C.D.,Zhang, T.,Wang, J.,Ding, X.,Yang, F.,Ying, G.,Yang, J.,Zhang, K.,Zhu, Y.,Yao, Z.,Yang, N.,Shi, L.
PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.
Sci Adv, 7:-, 2021

PubMed 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.

PubMed: 33952527
DOI: 10.1126/sciadv.abf7684

Experimental method

X-RAY DIFFRACTION (1.695 Å)