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 - Funding Information:
We thank NIEHS staff and core facilities: A. Moon, J. Krahn, and L. Pedersen (x-ray crystallography), C. Malone and B. Petrovich (anti-GFP sepharose and HEK293F cell culture), A. Janoshazi and J. Tucker (microscopy), A. Adams and K. Johnson (mass spectrometry), M. Sifre and C. Bortner (flow cytometry), and N. Gassman (UV microirradiation). Supported by NIH Intramural Research Program grants 1Z01ES102765 (R.S.W.), 1ZIAES050111-26 (R.E.L.), and ZES102488-09 (J.G.W.); Spanish and Andalusian Government grants SAF2010-21017, SAF2013-47343-P, SAF2014-55532-R, CVI-7948, and FEDER funds (F.C.-L.) and BES-2015-071672 (A.H.-R.); European Research Council grant ERC-CoG-2014-647359 (F.C.-L.); and University of Seville grant PIF-2011 (J.A.L.). The Advanced Photon Source SERCAT beamline is supported by the U.S. Department of Energy, Office of Basic Energy Sciences (DOE OBES) grant W-31-109-Eng-38. The Advanced Light Source is operated by Lawrence Berkeley National Laboratory on behalf of DOE OBES and the IDAT program, supported by the DOE Office of Biological and Environmental Research and NIH project MINOS (R01GM105404). CABIMER is supported by the Andalusian Government. Coordinates were deposited in the RCSB Protein Data Bank under 5TVP for TDP2-SUMO2-DNA and 5TVQ for TDP2-SUMO2. Author contributions: conceptualization, M.J.S., F.C.-L., and R.S.W.; methodology, M.J.S., J.G.W., G.A.M., F.C.-L., and R.S.W.; investigation, M.J.S., J.A.L., A.H.-R., L.R.B., J.G.W., A.M.M.-C., and G.A.M.; writing (original draft), M.J.S., F.C.-L., and R.S.W.; writing (reviewing and editing), M.J.S., J.A.L., J.G.W., G.A.M., F.C.-L., and R.S.W.; funding acquisition, F.C.-L., R.E.L., and R.S.W.; supervision, R.E.L., F.C.-L., and R.S.W. The authors declare no competing financial interests.
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
VL - 357
SP - 1412
EP - 1416
JO - Science
JF - Science
SN - 0036-8075
IS - 6358
ER -