PuSH - Publikationsserver des Helmholtz Zentrums München

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)
Verlagsversion Forschungsdaten 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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mesenchymal Transition; Ser46 Phosphorylation; Apoptotic Response; Breast-cancer; C-myc; Degradation; Stabilization; Fbw7; P53
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Zeitschrift Cell Death and Differentiation
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
Förderungen 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)