TY - JOUR
T1 - ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links
AU - Schellenberg, Matthew J.
AU - Lieberman, Jenna Ariel
AU - Herrero-Ruiz, Andrés
AU - Butler, Logan R.
AU - Williams, Jason G.
AU - Muñoz-Cabello, Ana M.
AU - Mueller, Geoffrey A.
AU - London, Robert E.
AU - Cortés-Ledesma, Felipe
AU - Williams, R. Scott
N1 - Publisher Copyright:
© 2017, American Association for the Advancement of Science. All rights reserved.
PY - 2017/9/29
Y1 - 2017/9/29
N2 - 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.
AB - 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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U2 - 10.1126/science.aam6468
DO - 10.1126/science.aam6468
M3 - Article
C2 - 28912134
AN - SCOPUS:85029595909
SN - 0036-8075
VL - 357
SP - 1412
EP - 1416
JO - Science
JF - Science
IS - 6358
ER -