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A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival

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dc.contributor.author Lara-Chica, Maribel
dc.contributor.author Correa-Sáez, Alejandro
dc.contributor.author Jiménez-Izquierdo, Rafael
dc.contributor.author Garrido-Rodríguez, Martín
dc.contributor.author Ponce, Francisco J.
dc.contributor.author Moreno, Rita
dc.contributor.author Morrison, Kimberley
dc.contributor.author Di Vona, Chiara, 1981-
dc.contributor.author Arató, Krisztina, 1981-
dc.contributor.author Jiménez-Jiménez, Carla
dc.contributor.author Morrugares, Rosario
dc.contributor.author Schmitz, M. Lienhard
dc.contributor.author Luna, Susana de la
dc.contributor.author Vega, Laureano de la
dc.contributor.author Calzado, Marco A.
dc.date.accessioned 2021-11-30T07:16:58Z
dc.date.available 2021-11-30T07:16:58Z
dc.date.issued 2022
dc.identifier.citation Lara-Chica M, Correa-Sáez A, Jiménez-Izquierdo R, Garrido-Rodríguez M, Ponce FJ, Moreno R, Morrison K, Di Vona C, Arató K, Jiménez-Jiménez C, Morrugares R, Schmitz ML, de la Luna S, de la Vega L, Calzado MA. A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival. Cell Death Differ. 2022;29:105-17. DOI: 10.1038/s41418-021-00845-5
dc.identifier.issn 1350-9047
dc.identifier.uri http://hdl.handle.net/10230/49091
dc.description.abstract The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin-Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. CDC25A in turn is able to control the phosphorylation of DYRK2 at several residues outside from its activation loop, thus affecting DYRK2 localization and activity. An inverse correlation between DYRK2 and CDC25A protein amounts was observed during cell cycle progression and in response to DNA damage, with CDC25A accumulation responding to the manipulation of DYRK2 levels or activity in either physiological scenario. Functional data show that the pro-survival activity of CDC25A and the pro-apoptotic activity of DYRK2 could be partly explained by the mutual regulation between both proteins. Moreover, DYRK2 modulation of CDC25A expression and/or activity contributes to the DYRK2 role in cell cycle regulation. Altogether, we provide evidence suggesting that DYRK2 and CDC25A mutually control their activity and stability by a feedback regulatory loop, with a relevant effect on the genotoxic stress pathway, apoptosis, and cell cycle regulation.
dc.description.sponsorship This work was funded by Ministerio de Ciencia e Innovación (SAF2016-75228-R to MAC and BFU2016-76141-P to SdlL) and by Cancer Research UK (C52419/A22869) to LdlV. MLC and ACS were supported by a FPU fellowship (FPU13/03393 and FPU18/00845, respectively) from the Ministerio de Educación y Formación Profesional.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Cell Death Differ. 2022;29:105-17
dc.rights © The Author(s) 2021. Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41418-021-00845-5
dc.subject.keyword Cell biology
dc.subject.keyword Proteins
dc.subject.keyword Proteomics
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75228-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-76141-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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