circRAB3IP modulates cell proliferation by reorganizing gene expression and mRNA processing in a paracrine manner
- Natasa Josipovic1,7,
- Karoline K. Ebbesen2,3,7,
- Anne Zirkel4,
- Adi Danieli-Mackay1,
- Christoph Dieterich5,
- Leo Kurian4,6,
- Thomas B. Hansen2 and
- Argyris Papantonis1,4
- 1Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
- 2Department of Molecular Biology and Genetics (MBG), Aarhus University, 8000 Aarhus, Denmark
- 3Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, 8000 Aarhus, Denmark
- 4Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- 5Bioinformatics and Systems Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- 6Institute of Neurophysiology, University of Cologne, 50931 Cologne, Germany
- Corresponding author: argyris.papantonis{at}med.uni-goettingen.de
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↵7 These authors contributed equally to this work.
Abstract
Circular RNAs are an endogenous long-lived and abundant noncoding species. Despite their prevalence, only a few circRNAs have been dissected mechanistically to date. Here, we cataloged nascent RNA-enriched circRNAs from primary human cells and functionally assigned a role to circRAB3IP in sustaining cellular homeostasis. We combined “omics” and functional experiments to show how circRAB3IP depletion deregulates hundreds of genes, suppresses cell cycle progression, and induces senescence-associated gene expression changes. Conversely, excess circRAB3IP delivered to endothelial cells via extracellular vesicles suffices for accelerating their division. We attribute these effects to an interplay between circRAB3IP and the general splicing factor SF3B1, which can affect transcript variant expression levels of cell cycle–related genes. Together, our findings link the maintenance of cell homeostasis to the presence of a single circRNA.
Keywords
- Received April 5, 2022.
- Accepted August 1, 2022.
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