Cotranscriptional exon skipping in the genotoxic stress response.
Pre-mRNA splicing is functionally coupled to transcription, and genotoxic stresses can enhance alternative exon inclusion by affecting elongating RNA polymerase II. We report here that various genotoxic stress inducers, including camptothecin (CPT), inhibit the interaction between Ewing's sarcoma proto-oncoprotein (EWS), an RNA polymerase II-associated factor, and YB-1, a spliceosome-associated factor. This results in the cotranscriptional skipping of several exons of the MDM2 gene, which encodes the main p53 ubiquitin ligase. This reversible exon skipping participates in the regulation of MDM2 expression that may contribute to the accumulation of p53 during stress exposure and its rapid shut-off when stress is removed. Finally, a splicing-sensitive microarray identified numerous exons that are skipped in response to CPT and EWS-YB-1 depletion. These data demonstrate genotoxic stress-induced alteration of the communication between the transcriptional and splicing machineries, which results in widespread exon skipping and plays a central role in the genotoxic stress response.
Dutertre
Martin
M
Institut National de Santé et de Recherche Médicale U590, Centre Léon Bérard, Lyon, France. martin.dutertre@inserm.fr
Sanchez
Gabriel
G
De Cian
Marie-Cécile
MC
Barbier
Jérôme
J
Dardenne
Etienne
E
Gratadou
Lise
L
Dujardin
Gwendal
G
Le Jossic-Corcos
Catherine
C
Corcos
Laurent
L
Auboeuf
Didier
D
D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004257:DNA Polymerase II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005091:Exons / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000502:physiology; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034802:RNA-Binding Protein EWS; D016159:Tumor Suppressor Protein p53; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D004257:DNA Polymerase II; D002166:Camptothecin