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

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

doi:10.1126/science.aam6468

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

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

Biochemistry and Molecular Biology

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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.

Original language	English (US)
Pages (from-to)	1412-1416
Number of pages	5
Journal	Science
Volume	357
Issue number	6358
DOIs	https://doi.org/10.1126/science.aam6468
State	Published - Sep 29 2017

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@article{e1ecd8410f1d415f837845c6f91cfcb4,

title = "ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links",

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.",

author = "Schellenberg, {Matthew J.} and Lieberman, {Jenna Ariel} and Andr{\'e}s Herrero-Ruiz and Butler, {Logan R.} and Williams, {Jason G.} and Mu{\~n}oz-Cabello, {Ana M.} and Mueller, {Geoffrey A.} and London, {Robert E.} and Felipe Cort{\'e}s-Ledesma and Williams, {R. Scott}",

note = "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: {\textcopyright} 2017, American Association for the Advancement of Science. All rights reserved.",

year = "2017",

month = sep,

day = "29",

doi = "10.1126/science.aam6468",

language = "English (US)",

volume = "357",

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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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JO - Science

JF - Science

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ER -

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

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