期刊
SCIENCE
卷 357, 期 6358, 页码 1412-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aam6468
关键词
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资金
- NIH Intramural Research Program grants [1Z01ES102765, 1ZIAES050111-26, ZES102488-09]
- Spanish Government [SAF2010-21017, SAF2013-47343-P, SAF2014-55532-R, CVI-7948]
- FEDER funds
- European Research Council [ERC-CoG-2014-647359]
- University of Seville [PIF-2011]
- U.S. Department of Energy, Office of Basic Energy Sciences (DOE OBES) grant [W-31-109-Eng-38]
- DOE Office of Biological and Environmental Research
- NIH project MINOS [R01GM105404]
- Andalusian Government
- Andalusian Government [SAF2010-21017, SAF2013-47343-P, SAF2014-55532-R, CVI-7948]
- [BES-2015-071672]
Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a split-SIM SUMO2 engagement platform. These findings uncover a ZATT-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
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