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Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2

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dc.contributor.authorSchellenberg, Matthew J
dc.contributor.authorAppel, C Denise
dc.contributor.authorRiccio, Amanda A
dc.contributor.authorButler, Logan R
dc.contributor.authorKrahn, Juno M
dc.contributor.authorLiebermann, Jenna A
dc.contributor.authorCortes-Ledesma, Felipe
dc.contributor.authorWilliams, R Scott
dc.contributor.funderUnited States Department of Health and Human Services
dc.contributor.funderNIH - National Institute of Environmental Health Sciences (NIEHS) (Estados Unidos)
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)
dc.date.accessioned2020-05-05T14:28:25Z
dc.date.available2020-05-05T14:28:25Z
dc.date.issued2020-05-01
dc.descriptionIntramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765 to R.S.W.]; Work in the F.C.L. lab is supported by Ministerio de Economía y Competitividad, Gobierno de España [SAF2017-89619-R, European Regional Development Fund]; European Research Council [ERC-CoG-2014-647359]; University of Seville Predoctoral Studentship [PIF-2011 to J.A.L.]; M.J.S. is supported by Mayo Clinic start-up funds and the Center for Biomedical Discovery new investigator funds; Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory; Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; SAXS data were collected at the Advanced Light Source (ALS), a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the Department of Energy, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by DOE Office of Biological and Environmental Research. Additional support comes from the National Institute of Health project ALS-ENABLE [P30 GM124169]; High-End Instrumentation Grant [S10OD018483]. Funding for open access charge: US government, Intramural NIH.es_ES
dc.description.abstractTyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 functions is unknown. Here, we show that TDP2 co-purifies with K63 and K27 poly-Ubiquitinated cellular proteins independently of, and separately from SUMOylated TOP2 complexes. Poly-ubiquitin chains of ≥ Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA-protein crosslinks in vitro. X-ray crystal structures and small-angle X-ray scattering analysis of TDP2-Ub complexes reveal that the TDP2 UBA domain binds K63-Ub3 in a 1:1 stoichiometric complex that relieves a UBA-regulated autoinhibitory state of TDP2. Our data indicates that that poly-Ub regulates TDP2-catalyzed TOP2-DPC removal, and TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ubiquitin interface.es_ES
dc.description.peerreviewedSíes_ES
dc.identifier.citationNucleic Acids Res. 2020. pii: gkaa318es_ES
dc.identifier.doi10.1093/nar/gkaa318es_ES
dc.identifier.e-issn1362-4962es_ES
dc.identifier.issn0305-1048es_ES
dc.identifier.journalNucleic acids researches_ES
dc.identifier.pubmedID32356875es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9906
dc.language.isoenges_ES
dc.publisherOxford University Press
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2017-89619-Res_ES
dc.relation.publisherversionhttps://doi.org/10.3390/10.1093/nar/gkaa318.es_ES
dc.repisalud.institucionCNIOes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleUbiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2es_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
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