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

Schellenberg, Matthew J.; Ariel Lieberman, Jenna; Herrero-Ruiz, Andres; Butler, Logan R.; Williams, Jason G.; Munoz-Cabello, Ana M.; Mueller, Geoffrey A.; London, Robert E.; Cortes-Ledesma, Felipe; Williams, R. Scott

Publicación: SCIENCE
2017
VL / 357 - BP / 1412 - EP / +
abstract
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.

Access level

Gold other, Green accepted

MENTIONS DATA