Journal
SCIENCE ADVANCES
Volume 7, Issue 19, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf7684
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [2019YFA0802003, 81972660, 81722036, 2019YFA0508902, 2018YFA0107004, 81502408, 82003004]
- Chinese Ministry of Science and Technology
- Tianjin Funds for Distinguished Young Scientists [17JCJQJC46100, 17JCJQJC45900]
- Excellent Talent Project of Tianjin Medical University
Ask authors/readers for more resources
The study reveals the crucial role of histone demethylase PHF8 in ATR activation and replication stress response, shedding light on the regulation of the assembly of TOPBP1-scaffolded protein complex.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available