7cmz
From Proteopedia
Crystal Structure of BRCT7/8 in Complex with the APS Motif of PHF8
Structural highlights
FunctionTOPB1_HUMAN Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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. PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.,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 CD, Zhang T, Wang J, Ding X, Yang F, Ying G, Yang J, Zhang K, Zhu Y, Yao Z, Yang N, Shi L Sci Adv. 2021 May 5;7(19):eabf7684. doi: 10.1126/sciadv.abf7684. Print 2021 May. PMID:33952527[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Cao C | Che SY | Ma S | Shi L | Yang N | Yao Z
