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Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39
Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy but requires high levels of the adaptor protein DCAF15. Consequently, novel approaches to deplete RBM39 in an DCAF15-independent manner are required. Here, we uncover that RBM39...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477243/ https://www.ncbi.nlm.nih.gov/pubmed/37666821 http://dx.doi.org/10.1038/s41467-023-40254-5 |
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author | Campagne, Sébastien Jutzi, Daniel Malard, Florian Matoga, Maja Romane, Ksenija Feldmuller, Miki Colombo, Martino Ruepp, Marc-David Allain, Frédéric H-T. |
author_facet | Campagne, Sébastien Jutzi, Daniel Malard, Florian Matoga, Maja Romane, Ksenija Feldmuller, Miki Colombo, Martino Ruepp, Marc-David Allain, Frédéric H-T. |
author_sort | Campagne, Sébastien |
collection | PubMed |
description | Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy but requires high levels of the adaptor protein DCAF15. Consequently, novel approaches to deplete RBM39 in an DCAF15-independent manner are required. Here, we uncover that RBM39 autoregulates via the inclusion of a poison exon into its own pre-mRNA and identify the cis-acting elements that govern this regulation. We also determine the NMR solution structures of RBM39’s tandem RNA recognition motifs (RRM1 and RRM2) bound to their respective RNA targets, revealing how RRM1 recognises RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG. Our results support a model where RRM2 selects the 3’-splice site of a poison exon and the RRM3 and RS domain stabilise the U2 snRNP at the branchpoint. Our work provides molecular insights into RBM39-dependent 3’-splice site selection and constitutes a solid basis to design alternative anti-cancer therapies. |
format | Online Article Text |
id | pubmed-10477243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104772432023-09-06 Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 Campagne, Sébastien Jutzi, Daniel Malard, Florian Matoga, Maja Romane, Ksenija Feldmuller, Miki Colombo, Martino Ruepp, Marc-David Allain, Frédéric H-T. Nat Commun Article Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy but requires high levels of the adaptor protein DCAF15. Consequently, novel approaches to deplete RBM39 in an DCAF15-independent manner are required. Here, we uncover that RBM39 autoregulates via the inclusion of a poison exon into its own pre-mRNA and identify the cis-acting elements that govern this regulation. We also determine the NMR solution structures of RBM39’s tandem RNA recognition motifs (RRM1 and RRM2) bound to their respective RNA targets, revealing how RRM1 recognises RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG. Our results support a model where RRM2 selects the 3’-splice site of a poison exon and the RRM3 and RS domain stabilise the U2 snRNP at the branchpoint. Our work provides molecular insights into RBM39-dependent 3’-splice site selection and constitutes a solid basis to design alternative anti-cancer therapies. Nature Publishing Group UK 2023-09-04 /pmc/articles/PMC10477243/ /pubmed/37666821 http://dx.doi.org/10.1038/s41467-023-40254-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Campagne, Sébastien Jutzi, Daniel Malard, Florian Matoga, Maja Romane, Ksenija Feldmuller, Miki Colombo, Martino Ruepp, Marc-David Allain, Frédéric H-T. Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title | Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title_full | Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title_fullStr | Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title_full_unstemmed | Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title_short | Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39 |
title_sort | molecular basis of rna-binding and autoregulation by the cancer-associated splicing factor rbm39 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477243/ https://www.ncbi.nlm.nih.gov/pubmed/37666821 http://dx.doi.org/10.1038/s41467-023-40254-5 |
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