2026-04-14T08:51:41Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/695232025-12-12T03:40:29Zcom_2072_6col_2072_452952

Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors Damodaran, Arun Prasath Gavard, Olivia Gagné, Jean-Philippe Rogalska, Malgorzata Behera, Amit K. Mancini, Estefanía Bertolin, Giulia Courthéoux, Thibault Kumari, Bandana Cailloce, Justine Méreau, Agnès Poirier, Guy G. Valcárcel, J. (Juan) Gonatopoulos-Pournatzis, Thomas Watrin, Erwan Prigent, Claude Aurora-A CLK1 RNA SR protein Cancer Cell cycle hnRNP proteins Kinase Mitosis Proteomics Splicing The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including several splicing factors. Supporting a role in alternative splicing, we found that Aurora-A localizes to nuclear speckles, the storehouse of splicing proteins. Aurora-A interacts with and phosphorylates splicing factors both in vitro and in vivo, suggesting that it regulates alternative splicing by modulating the activity of these splicing factors. Consistently, Aurora-A inhibition significantly impacts the alternative splicing of 505 genes, with RNA motif analysis revealing an enrichment for Aurora-A interacting splicing factors. Additionally, we observed a significant positive correlation between the splicing events regulated by Aurora-A and those modulated by its interacting splicing factors. An interesting example is represented by CLK1 exon 4, which appears to be regulated by Aurora-A through SRSF3. Collectively, our findings highlight a broad role of Aurora-A in the regulation of alternative splicing. Work by C. P.'s team is supported by the University of Rennes 1, the CNRS, and the Ligue Nationale Contre le Cancer “Équipe labellisée 2014-2017” and ligue35. The PhD salary of A. P. D. and the post-doc salary of T. C are supported by the Ligue Nationale Contre le Cancer and the Bretagne region. This work is also supported by the NCI/NIH Intramural Research Program (Project ZIABC012019). Work in J. V. lab was supported by Spanish Ministry of Science and Innovation (PID2020-114630GB-100/AEI/10.13039/501100011033), EMBL Partnership and Severo Ochoa Centre of Excellence (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme. 2025-02-07T08:08:49Z 2025-02-07T08:08:49Z 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Damodaran AP, Gavard O, Gagné JP, Rogalska ME, Behera AK, Mancini E, et al. Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors. J Biol Chem. 2024 Nov 17;301(1):108000. DOI: 10.1016/j.jbc.2024.108000 0021-9258 http://hdl.handle.net/10230/69523 http://dx.doi.org/10.1016/j.jbc.2024.108000 eng J Biol Chem. 2024 Nov 17;301(1):108000 info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-100 info:eu-repo/grantAgreement/ES/2PE/CEX2020-001049-S © 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Elsevier