Abstract
The tumor suppressor protein p53 orchestrates cellular responses to stress by regulating the transcription of target genes involved in processes such as cell cycle control, DNA damage repair and apoptosis. The protein kinase DYRK1B, known to promote cancer cell survival and contribute to DNA damage repair, is overexpressed in various tumor types. Here, we demonstrate that expression of DYRK1B - but not its closely related paralog DYRK1A - is upregulated by cytostatic drugs (Actinomycin D, Doxorubicin) in multiple cancer cell lines. This induction required functional p53 and was mediated by p53-dependent activation of the transcription factor RFX7. Furthermore, we show that DYRK1B physically interacts with RFX7 and counteracts its activation by p53, thereby establishing a negative feedback loop that attenuates RFX7-dependent gene expression. This inhibitory effect of DYRK1B was strictly dependent on its catalytic activity and could be blocked by using small-molecule DYRK1 inhibitors. In conclusion, our study identifies DYRK1B as an indirect p53 target that suppresses p53-mediated activation of RFX7. These findings suggest that pharmacological inhibition of DYRK1B may represent a therapeutic strategy to enhance RFX7 tumor suppressor function.
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Data availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the data set identifier PXD067702. The RNA-seq datasets analyzed in this study are provided as supplementary information. Publicly available data used in this study originated from TNMplot (https://tnmplot.com/analysis/) and TargetGeneReg 2.0 web atlas (http://www.targetgenereg.org/). All other data generated and/or analyzed during the current study are included in this published article and its supplementary information files.
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Acknowledgements
We wish to thank Tanja Woopen, Ragini Kushwaha and Soraya Sester for help with the production of lentiviruses and cell line development and qPCR experiments, Anushka Kudaliyanage for excellent technical assistance with the proteomics experiments, and Sebastian Giesselmann for excellent technical assistance with the RNA-seq experiments. Valuable research reagents (cell lines and plasmids) were kindly provided by Greta Guarda (Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland) and our colleagues at the RWTH Aachen University (Edgar Dahl, Institute of Pathology; Athanassios Fragoulis, Department of Anatomy and Cell Biology; Rudolf Leube, Institute of Molecular and Cellular Anatomy). DYR684 was a kind gift of Christopher Hulme (University of Arizona, The College of Pharmacy, Department of Pharmacology & Toxicology).
Funding
This research was supported by the German Research Foundation (DFG) projects 424656244 and 520339551 (BE 1967/5-1 and BE 1967/6-1, to WB), by the German Federal Ministry of Education and Research (01KD2435, to SD), and by the START-Program of the Faculty of Medicine of the RWTH Aachen University (Innenauftragsnummer 692214, Az 20/22, to GW). Open Access funding enabled and organized by Projekt DEAL.
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GW planned and conducted the majority of the experiments, analyzed the data, and coordinated the collaborative work. KS performed selected Western blot and immunoprecipitation experiments and conducted the chemosensitivity assays. GW, KS and PH generated the A549 tetON RFX7 and RFX7-KO cell lines. SD carried out the modeling of protein–protein interactions. GW and FK planned and conducted RNA-seq experiments and related data analysis. GW, SK, and FM conducted the proteomics and interactomics analyses and interpreted the results. GW and JW performed the statistical evaluation. GW and WB were responsible for the overall experimental design, data interpretation, and writing of the manuscript. All authors provided feedback on the manuscript and approved the final version.
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GW, KS and WB are co-inventors of patents on DYRK PROTACs (PCT/US2023/080099 and PCT/US2024/050636).
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Wilms, G., Schwandt, K., Düsterhöft, S. et al. The protein kinase DYRK1B is a p53 target gene and functions as a negative feedback regulator of the transcription factor RFX7. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08660-x
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DOI: https://doi.org/10.1038/s41419-026-08660-x
