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.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aminoacyltransferases
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Animals
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Biocatalysis
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Catalytic Domain
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DNA / genetics
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DNA / metabolism
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DNA Damage*
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DNA Repair*
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism*
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DNA-Binding Proteins
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Etoposide / pharmacology
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Gene Knockdown Techniques
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HEK293 Cells
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Humans
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Immunoprecipitation
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphoric Diester Hydrolases
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Small Ubiquitin-Related Modifier Proteins / metabolism
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Sumoylation
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Topoisomerase II Inhibitors / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Bacterial Proteins
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DNA-Binding Proteins
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Luminescent Proteins
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Nuclear Proteins
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Recombinant Proteins
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SUMO2 protein, human
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Saccharomyces cerevisiae Proteins
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Small Ubiquitin-Related Modifier Proteins
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Topoisomerase II Inhibitors
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Transcription Factors
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yellow fluorescent protein, Bacteria
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Etoposide
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DNA
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Aminoacyltransferases
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ZNF451 protein, human
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ZNF451 protein, mouse
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Ubiquitin-Protein Ligases
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Phosphoric Diester Hydrolases
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TDP2 protein, human
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DNA Topoisomerases, Type II