A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response

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  • dc.contributor.author Roewenstrunk, Julia Maria, 1981-
  • dc.contributor.author Di Vona, Chiara, 1981-
  • dc.contributor.author Chen, Jie
  • dc.contributor.author Borràs, Eva
  • dc.contributor.author Dong, Chao
  • dc.contributor.author Arató, Krisztina, 1981-
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Huen, Michael S. Y.
  • dc.contributor.author Luna Gargantilla, Susana de la
  • dc.date.accessioned 2019-07-19T08:33:52Z
  • dc.date.available 2019-07-19T08:33:52Z
  • dc.date.issued 2019
  • dc.description.abstract Dysregulation of the DYRK1A protein kinase has been associated with human disease. On the one hand, its overexpression in trisomy 21 has been linked to certain pathological traits of Down syndrome, while on the other, inactivating mutations in just one allele are responsible for a distinct yet rare clinical syndrome, DYRK1A haploinsufficiency. Moreover, altered expression of this kinase may also provoke other human pathologies, including cancer and diabetes. Although a few DYRK1A substrates have been described, its upstream regulators and downstream targets are still poorly understood, an information that could shed light on the functions of DYRK1A in the cell. Here, we carried out a proteomic screen using antibody-based affinity purification coupled to mass spectrometry to identify proteins that directly or indirectly bind to endogenous DYRK1A. We show that the use of a cell line not expressing DYRK1A, generated by CRISPR/Cas9 technology, was needed in order to discriminate between true positives and non-specific interactions. Most of the proteins identified in the screen are novel candidate DYRK1A interactors linked to a variety of activities in the cell. The in-depth characterization of DYRK1A's functional interaction with one of them, the E3 ubiquitin ligase RNF169, revealed a role for this kinase in the DNA damage response. We found that RNF169 is a DYRK1A substrate and we identified several of its phosphorylation sites. In particular, one of these sites appears to modify the ability of RNF169 to displace 53BP1 from sites of DNA damage. Indeed, DYRK1A depletion increases cell sensitivity to ionizing irradiation. Therefore, our unbiased proteomic screen has revealed a novel activity of DYRK1A, expanding the complex role of this kinase in controlling cell homeostasis.
  • dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) BFU2013-44513 and BFU2016-76141-P, and the Secretariat of Universities and Research-Generalitat de Catalunya (2014SGR674). Proteomic analysis was carried out at the CRG/UPF Proteomics Unit, a member of the ProteoRed PRB3 consortium that is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. J.R. is a FPI predoctoral fellow (BES-2011-045867). We also acknowledge the support of the Generalitat de Catalunya: CERCA Programme and Grups de Recerca Reconocida Programme (2017SGR595 and 2017SGR1163)
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Roewenstrunk J, Di Vona C, Chen J, Borras E, Dong C, Arató K et al. A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response. Sci Rep. 2019 Apr 12;9(1):6014. DOI: 10.1038/s41598-019-42445-x
  • dc.identifier.doi http://dx.doi.org/10.1038/s41598-019-42445-x
  • dc.identifier.issn 2045-2322
  • dc.identifier.uri http://hdl.handle.net/10230/42072
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Scientific Reports. 2019 Apr 12;9(1):6014
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44513
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-76141-P
  • dc.rights © Springer Nature Publishing AG. http://dx.doi.org/10.1038/s41598-019-42445-x. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Proteòmica
  • dc.subject.other Gens
  • dc.subject.other ADN
  • dc.title A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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