Schellenberg, Matthew JLieberman, Jenna ArielHerrero-Ruiz, AndresButler, Logan RWilliams, Jason GMuñoz-Cabello, Ana MMueller, Geoffrey ALondon, Robert ECortes-Ledesma, FelipeWilliams, R Scott2023-01-252023-01-252017-09-29Schellenberg MJ, Lieberman JA, Herrero-Ruiz A, Butler LR, Williams JG, Muñoz-Cabello AM, et al. ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science. 2017 Sep 29;357(6358):1412-1416.http://hdl.handle.net/10668/11582Topoisomerase 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.enTOP2 cleavage complex resolutionSUMOylation in DNA repairZATT-TDP2 signaling axisNon-proteasomal DNA-protein crosslink repairSUMO2 engagement platformAnticancer drug-induced genotoxicityAminoacyltransferasesAnimalsBacterial ProteinsBiocatalysisCatalytic DomainDNADNA DamageDNA RepairDNA Topoisomerases, Type IIDNA-Binding ProteinsEtoposideGene Knockdown TechniquesHEK293 CellsHumansImmunoprecipitationLuminescent ProteinsMiceNuclear ProteinsPhosphoric Diester HydrolasesRecombinant ProteinsSaccharomyces cerevisiae ProteinsSmall Ubiquitin-Related Modifier ProteinsSumoylationTopoisomerase II InhibitorsTranscription FactorsUbiquitin-Protein Ligasesresearch article28912134Restricted AccessTopoisomerasas del ADN tipo IIDaño al ADNReparación del ADNLigasas de proteínas ubiquitinaProteína SUMO-1ProteólisisFosfodiesterasa de ADN tirosil10.1126/science.aam64681095-9203PMC5623066https://europepmc.org/articles/pmc5623066?pdf=renderhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623066/pdf