ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links

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Science  29 Sep 2017:
Vol. 357, Issue 6358, pp. 1412-1416
DOI: 10.1126/science.aam6468

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Resolving a DNA-protein cross-link

Topoisomerase 2 (TOP2) creates DNA double-strand breaks to regulate DNA topology and is critical for processes such as replication and transcription. A covalent complex between TOP2 and DNA (TOP2cc) is an intermediate in the reaction that can be trapped by drugs. Schellenberg et al. show how the SUMO ligase ZATT promotes the resolution of TOP2cc by means of tyrosyl-DNA phosphoesterase 2 (TDP2), both by enhancing recruitment of TDP2 to SUMOylated TOP2 and by enhancing the hydrolase activity of TDP2.

Science, this issue p. 1412


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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