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Suanes-Cobos, L.* ; Aguilera-Ventura, I.* ; Torres-Ramos, M.* ; Serrano-Yubero, A.* ; Moreno Fernández-Aliseda, C.* ; Fernández, S.* ; Garrido-Rodríguez, M.* ; de la Luna, S.* ; Prieto-Garcia, C.* ; Diefenbacher, M. ; Mejias-Perez, E.* ; Calzado, M.A.*

A novel feedback loop between DYRK2 and USP28 regulates cancer homeostasis and DNA damage signaling.

Cell Death Differ., DOI: 10.1038/s41418-025-01565-w (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Posttranslational modifications, such as ubiquitination and phosphorylation, play pivotal roles in regulating protein stability in response to cellular stress. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and ubiquitin-specific peptidase 28 (USP28) are critical regulators of cell cycle progression, DNA damage response, and oncogenic signaling. However, their functional interplay remains largely unexplored. Here, we describe a novel bidirectional regulatory mechanism between DYRK2 and USP28 that integrates DNA damage response and ubiquitin-mediated protein degradation. We demonstrate that DYRK2 phosphorylates USP28, promoting its ubiquitination and proteasomal degradation in a kinase activity-independent manner, thereby contributing to the maintenance of oncogenic protein homeostasis. Conversely, USP28 functions as a deubiquitinase for DYRK2, stabilizing its protein levels and enhancing its kinase activity. Notably, we show that DYRK2 interacts and co-localizes with USP28, with the 521-541 DYRK2 region, particularly residue T525, playing a crucial role in USP28-mediated DYRK2 stabilization. Functionally, this reciprocal regulation modulates p53 signaling, influencing apoptotic responses to DNA damage. DYRK2-mediated phosphorylation of p53 at S46 is significantly reduced upon USP28 depletion, suggesting that USP28 facilitates DYRK2-dependent apoptosis. Additionally, our results highlight a complex regulatory axis involving USP28 and DYRK2, with implications for oncogenic cell death and genomic stability. Overall, our findings uncover a novel feedback loop in which DYRK2 and USP28 dynamically regulate each other to control proto-oncoprotein homeostasis and DNA damage signaling. This interplay offers potential therapeutic opportunities for targeting cancers with dysregulated ubiquitination and genomic instability.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mesenchymal Transition; Ser46 Phosphorylation; Apoptotic Response; Breast-cancer; C-myc; Degradation; Stabilization; Fbw7; P53
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Journal Cell Death and Differentiation
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
Grants Junta de Andalucia-Consejeria de Universidad, Investigacion e Innovacion
Junta de Andalucia-Consejeria de Conocimiento, Investigacion y Universidad
Consejeria de Salud
Scientific Foundation of the Spanish Association Against Cancer
Ayuda Ramon y Cajal from the Spanish Ministerio de Ciencia e Innovacion
FPU fellowship from the Spanish Ministerio de Educacion y Formacion Profesional
Fundacion Cientifica de la Asociacion Espanola contra el Cancer
Spanish Ministerio de Ciencia, Innovacion y Universidades (MICINN)