Lara-Chica, MaribelCorrea-Sáez, AlejandroJiménez-Izquierdo, RafaelGarrido-Rodríguez, MartínPonce, Francisco J.Moreno, RitaMorrison, KimberleyDi Vona, Chiara, 1981-Arató, Krisztina, 1981-Jiménez-Jiménez, CarlaMorrugares, RosarioSchmitz, M. LienhardLuna, Susana de laVega, Laureano de laCalzado, Marco A.2021-11-302021-11-302022Lara-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/s41418-021-00845-51350-9047http://hdl.handle.net/10230/49091The 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41418-021-00845-5Cell biologyProteinsProteomicsinfo:eu-repo/semantics/openAccess