7CMZ

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

7CMZ の概要

• エントリーDOI: 10.2210/pdb7cmz/pdb
• 分子名称: DNA topoisomerase 2-binding protein 1, Histone lysine demethylase PHF8, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: topbp1, protein binding-hydrolase complex, protein binding/hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28544.43

構造登録者

Che, S.Y.,Ma, S.,Cao, C.,Yao, Z.,Shi, L.,Yang, N. (登録日: 2020-07-29, 公開日: 2021-03-17, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.695 Å)