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Circular RNAs (circRNAs) are widely expressed in eukaryotes and are regulated in many biological processes. Although several studies indicate their activity as microRNA (miRNA) and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that the widely expressed circZNF609 directly interacts with several mRNAs and increases their stability and/or translation by favoring the recruitment of the RNA-binding protein ELAVL1. Particularly, the interaction with CKAP5 mRNA, which interestingly overlaps the back-splicing junction, enhances CKAP5 translation, regulating microtubule function in cancer cells and sustaining cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity of several cancer cell lines to different microtubule-targeting chemotherapeutic drugs and that locked nucleic acid (LNA) protectors against the pairing region on circZNF609 phenocopy such effects. These data set an example of how the small effects tuned by circZNF609 /CKAP5 mRNA interaction might have a potent output in tumor growth and drug response. [Display omitted] • circZNF609 interacts with CKAP5 , UPF2 , and SRRM1 mRNAs in vivo • circZNF609-mRNA interaction increases ELAVL1 loading on the mRNAs • ELAVL1 loading by circZNF609 regulates stability and translation of its targets • CAKP5 regulation alters MT dynamics, sensitizing cells to chemotherapeutic drugs In this article, Rossi et al. provide an interesting mechanism in which circZNF609-mRNA interaction increases translation, and among them, CKAP5 is a key factor in microtubule dynamics stability. The authors show how the disruption of RNA-RNA interactions is able to alter microtubule dynamics, sensitizing rhabdomyosarcoma cells to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

N 6 -methyladenosine (m 6 A) is an RNA modification well-known for its contribution to different processes controlling RNA metabolism, including splicing, stability, and translation of mRNA. Conversely, the role of m 6 A on the biogenesis and function of circular RNAs (circRNAs) has yet to be addressed. circRNAs belong to a class of covalently closed transcripts produced via a back-splicing reaction whereby a downstream 5' splice donor site fuses to an upstream 3' splice acceptor site. Starting from circ-ZNF609 as a study case, we discover that specific m 6 As control its accumulation and that METTL3 and YTHDC1 are required to direct the back-splicing reaction. This feature is shared with other circRNAs because we find a significant direct correlation among METTL3 requirement, YTHDC1 binding, and the ability of m 6 A exons to undergo back-splicing. Finally, because circ-ZNF609 displays the ability to be translated, we show that m 6 A modifications, through recognition by YTHDF3 and eIF4G2, modulate its translation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)