ZATT (ZNF451)-Mediated Resolution of Topoisomerase 2 DNA-Protein Crosslinks
Topoisomerase 2 (TOP2) DNA transactions are essential for life, and 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 crosslinks are resolved is uncle...
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Veröffentlicht in: | Science (American Association for the Advancement of Science) 2017-09, Vol.357 (6358), p.1412-1416 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Topoisomerase 2 (TOP2) DNA transactions are essential for life, and 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 crosslinks are resolved is unclear. Here, we show that the SUMO 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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ISSN: | 0036-8075 1095-9203 |
DOI: | 10.1126/science.aam6468 |