%0 Journal Article
%A Suanes-Cobos, Lucía
%A Aguilera-Ventura, Irene
%A Torres-Ramos, Miguel
%A Serrano-Yubero, Alejandra
%A Moreno Fernández-Aliseda, Claudia
%A Fernández, Silvia
%A Garrido-Rodríguez, Martín
%A de la Luna, Susana
%A Prieto-Garcia, Cristian
%A Diefenbacher, Markus E
%A Mejías-Pérez, Ernesto
%A Calzado, Marco A
%T A novel feedback loop between DYRK2 and USP28 regulates cancer homeostasis and DNA damage signaling.
%J Cell death and differentiation
%V nn
%@ 1350-9047
%C [London]
%I Springer Nature
%M DKFZ-2025-01783
%P nn
%D 2025
%Z epub
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40858801
%R 10.1038/s41418-025-01565-w
%U https://inrepo02.dkfz.de/record/304120