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

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.

Source: ScienceNOW - September 28, 2017 Category: Science Authors: Schellenberg, M. J., Lieberman, J. A., Herrero-Ruiz, A., Butler, L. R., Williams, J. G., Munoz-Cabello, A. M., Mueller, G. A., London, R. E., Cortes-Ledesma, F., Williams, R. S. Tags: Molecular Biology reports Source Type: news