AURORA A interacts with DICER and SETD2 to promote S-phase progression
The oncogenic kinase AURORA A is essential for mitotic progression, and its catalytic inhibition arrests cells at the G2/M-transition. Unexpectedly, degradation of AURORA A by PROTACs (proteolysis targeting chimeras) induces profound S-phase defects, revealing a non-catalytic scaffolding function of AURORA A. To dissect this function, we profile the AURORA A S-phase interactome and identify multiple RNA-binding proteins not characterized as AURORA A substrates. Among these, the ribonuclease DICER directly associates with AURORA A to form an abundant nuclear complex. RNA degradation shifts AURORA A, DICER, and additional RNA-binding proteins from heavy to light gradient fractions, implicating RNA-dependent complex function. In contrast, PROTAC-mediated depletion of AURORA A alters the gradient migration behavior and chromatin association of the histone methyltransferase SETD2, which is known to prevent spurious transcription. These findings reveal a dual-output model for the S-phase AURORA A complex: First, RNA-binding proteins are recruited to R-loops, which may arise from transcription-replication conflicts. DICER then processes the R-loop, while AURORA A simultaneously recruits SETD2, which facilitates efficient resolution of replicative stress by preventing spurious transcription.
Authors
- Bikash Adhikari (ORCID: https://orcid.org/0000-0002-9064-0356)
- Pranjali Bhandare (ORCID: https://orcid.org/0000-0002-2263-6515)
- Katharina Schneider (ORCID: https://orcid.org/0009-0009-4594-1609)
- Mathias Diebold (ORCID: https://orcid.org/0000-0002-7595-3901)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Gabriele Büchel (ORCID: https://orcid.org/0000-0001-7070-7341)
- Stephanie Wilhelm (ORCID: https://orcid.org/0000-0002-1066-6565)
- Tina Daunke (ORCID: https://orcid.org/0000-0002-1062-1076)
- Andreas Schlösser (ORCID: https://orcid.org/0000-0003-0612-9932)
- Yiliam Cruz-Garcia
- Martin L. Sos (ORCID: https://orcid.org/0000-0002-2868-100X)
- Bernhard Küster (ORCID: https://orcid.org/0000-0002-9094-1677)
- Anneli Gebhardt
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Julia Hofstetter (ORCID: https://orcid.org/0000-0003-4496-2394)
- Lasse Hoffmann
- M. Vogt (ORCID: https://orcid.org/0000-0002-4525-2901)
- Nevenka Dudvarski-Stankovic
- Nicola Berner
- Juliane Müller
- Stephanie Lamer
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- Frankfurt Institute for Advanced Studies (DE)
- LMU Klinikum (DE)
- Hochschule für Angewandte Wissenschaften Kiel (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Clinical Research Center Kiel (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-06-30
- DOI
- https://doi.org/10.1038/s44319-026-00850-0
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- European Research Council