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CircZNF609 regulates microtubule dynamics ad tumorigenicity by sustaining CKAP5 protein levels.

ABSTRACT: Circular RNAs (circRNAs) are widely expressed in eukaryotes and highly regulated in a myriad of biological processes. While many studies indicate their activity as miRNA and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that a widely expressed circRNA, circZNF609, directly interacts with several mRNAs and increases their stability and/or translation by favouring the recruitment of the RNA-binding protein ELAVL1. Specifically, the interaction with Ckap5 mRNA, that interestingly overlaps the back-splicing junction, regulates microtubule homeostasis in several cancer cell lines and sustains cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity to several microtubule-targeting cancer drugs in the regulation of microtubule metabolism and that LNA protectors against the Ckap5 pairing region on circZNF609 phenocopies such activity. These data set an example of how the small effects tuned by circZNF609/Ckap5 mRNA interaction might have potent output in tumour growth and drug response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174172 | GEO | 2021/12/13

REPOSITORIES: GEO

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Project description:The 3' untranslated region (3'UTR) of mRNA plays several important roles in post-transcriptional gene regulation. Some of its functions include regulating mRNA stability by polyadenylation and microRNAs. However, the overall function of the Gata1 3’UTR in mammals has not been defined. In this study, we used CRISPR/CAS9 technology to knock out the sequence of the mouse Gata1 3’UTR. We found a defect in erythropoiesis in mutant mice, evidenced by macrocytic anemia at the baseline. Ablation of Gata1 3’UTR also resulted in a reduced number of erythroid precursors that might be associated with the cell cycle, especially G2/M disruption in fetal livers. Mechanistically, deletion of the Gata1 3’UTR destabilizes the Gata1 mRNA and ultimately reduces Gata1 protein levels. The low stability of the Gata1 mRNA is unlikely to be caused by the loss of binding of microRNAs or lack of polyadenylation; rather, in part, by the dissociation of AU-rich elements in the 3’UTR with a trans-activating factor Elavl1. Specifically, we transcribed Gata1 3’UTR in vitro and performed an RNA pulldown assay followed by mass spectrometry to profile the proteins that bind the 3’UTR. Gene Ontology analysis demonstrated that several proteins specifically targeting the 3’UTR were found to potentially bind Gata1 3’UTR, among which Elavl1 was in almost all categories related to mRNA stabilization. Western blotting and RNA immunoprecipitation confirmed the direct interaction of Gata1 3’UTR with Elavl1. Manipulation of Elavl1 activity and protein levels by the small molecule inhibitor Dihydro-tanshinone-I and Elavl1 overexpression in fetal liver erythroblasts confirmed Elavl1 as a stabilizing factor for Gata1 mRNA. Our findings shed light on the functional significance of the 3’UTR of Gata1 mRNA in the context of erythroid development. More importantly, our findings highlight the complexity and diversity of regulatory mechanisms that govern Gata1 mRNA stability and precise expression at the post-transcriptional levels. In addition, our findings prove that miRNAs are not always essential in vivo for controlling transcription factor levels to maintain body homeostasis.

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CircZNF609 regulates microtubule dynamics ad tumorigenicity by sustaining CKAP5 protein levels.

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