دورية أكاديمية
Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation
| العنوان: | Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation |
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| المؤلفون: | Vincent Jonchère, Hugo Montémont, Enora Le Scanf, Aurélie Siret, Quentin Letourneur, Emmanuel Tubacher, Christophe Battail, Assane Fall, Karim Labreche, Victor Renault, Toky Ratovomanana, Olivier Buhard, Ariane Jolly, Philippe Le Rouzic, Cody Feys, Emmanuelle Despras, Habib Zouali, Rémy Nicolle, Pascale Cervera, Magali Svrcek, Pierre Bourgoin, Hélène Blanché, Anne Boland, Jérémie Lefèvre, Yann Parc, Mehdi Touat, Franck Bielle, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos, Gaël Quéré, Gwendal Dujardin, Marc Blondel, Cédric Le Maréchal, Romain Cohen, Thierry André, Florence Coulet, Pierre de la Grange, Aurélien de Reyniès, Jean-François Fléjou, Florence Renaud, Agusti Alentorn, Laurent Corcos, Jean-François Deleuze, Ada Collura, Alex Duval |
| المصدر: | Genome Biology, Vol 25, Iss 1, Pp 1-26 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Biology (General) LCC:Genetics |
| مصطلحات موضوعية: | Colorectal cancer, Mismatch repair deficiency, Microsatellite instability, Whole-exome and RNA sequencing, Alternative splicing, Polypyrimidine U2AF binding site, Biology (General), QH301-705.5, Genetics, QH426-470 |
| الوصف: | Abstract Background Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. Results Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. Conclusions Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1474-760X |
| Relation: | https://doaj.org/toc/1474-760X |
| DOI: | 10.1186/s13059-024-03340-5 |
| URL الوصول: | https://doaj.org/article/87efc7be65b6480c8bf4509103a6aab4 |
| رقم الأكسشن: | edsdoj.87efc7be65b6480c8bf4509103a6aab4 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1474760X |
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| DOI: | 10.1186/s13059-024-03340-5 |