Aurora-A phosphorylates splicing factors and regulates alternative splicing

Damodaran, A. P.; Gavard, O.; Gagne, J.-P.; Rogalska, M. E.; Mancini, E.; Courtheoux, T.; Cailloce, J.; Mereau, A.; Poirier, G. G.; Valcarcel, J.; Watrin, E.; Prigent, C.

doi:10.1101/2020.11.04.368498

bioRxiv · 10.1101/2020.11.04.368498

Aurora-A phosphorylates splicing factors and regulates alternative splicing

Damodaran, A. P.·Gavard, O.·Gagne, J.-P.·Rogalska, M. E.·Mancini, E.·Courtheoux, T.·Cailloce, J.·Mereau, A.·Poirier, G. G.·Valcarcel, J.·Watrin, E.·Prigent, C.

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Abstract

Aurora-A kinase is well known to regulate progression through mitosis. However, the kinase also performs additional functions that could explain the failure of its inhibitors to be effective in cancer treatments. To identify these functions, we applied a proteomics approach to search for interactors of Aurora-A. We found a large number of proteins involved in pre-mRNA splicing, strongly suggesting an important role for Aurora-A in this biological process. Consistently, we first report the subcellular localization of Aurora-A in nuclear speckles, the storehouse of splicing proteins. We also demonstrate direct interaction of Aurora-A with RRM domain-containing splicing factors such as hnRNP and SR proteins and their phosphorylation in vitro. Further, RNA-sequencing analysis following pharmacological inhibition of Aurora-A resulted in alternative splicing changes corresponding to 505 genes, including genes with functions regulated by Aurora-A kinase. Finally, we report enrichment of RNA motifs within the alternatively spliced regions affected by Aurora-A kinase inhibition which are bound by Aurora-A interacting splicing factors, suggesting that Aurora-A regulates alternative splicing by modulating the activity of these interacting splicing factors. Overall our work identified Aurora-A as a novel splicing kinase and for the first time, describes a broad role of Aurora-A in regulating alternative splicing.

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Damodaran, A. P., Gavard, O., Gagne, J.-P., Rogalska, M. E., Mancini, E., Courtheoux, T., Cailloce, J., Mereau, A., Poirier, G. G., Valcarcel, J., Watrin, E., Prigent, C.. 2020-11-04. Aurora-A phosphorylates splicing factors and regulates alternative splicing. https://doi.org/10.1101/2020.11.04.368498

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