A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy
| Autor: | Emma Bondy-Chorney, Andréanne Didillon, Gabriel Sanchez, Jocelyn Côté, Bernard J. Jasmin, Geneviève Paris, Janik Laframboise |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Protein-Arginine N-Methyltransferases Nonsense-mediated decay Biology Cell Line Muscular Atrophy Spinal 03 medical and health sciences Exon Mice Genetics medicine Animals Humans RNA Messenger Motor Neurons Messenger RNA Alternative splicing Gene regulation Chromatin and Epigenetics Intron Spinal muscular atrophy Exons medicine.disease SMA Molecular biology Introns Cell biology Nonsense Mediated mRNA Decay Mice Inbred C57BL Alternative Splicing 030104 developmental biology Spinal Cord RNA splicing Codon Terminator Trans-Activators RNA Helicases |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | Loss of 'Survival of Motor Neurons' (SMN) leads to spinal muscular atrophy (SMA), a disease characterized by degeneration of spinal cord alpha motor neurons, resulting in muscle weakness, paralysis and death during early childhood. SMN is required for assembly of the core splicing machinery, and splicing defects were documented in SMA. We previously uncovered that Coactivator-Associated Methyltransferase-1 (CARM1) is abnormally up-regulated in SMA, leading to mis-regulation of a number of transcriptional and alternative splicing events. We report here that CARM1 can promote decay of a premature terminating codon (PTC)-containing mRNA reporter, suggesting it can act as a mediator of nonsense-mediated mRNA decay (NMD). Interestingly, this pathway, while originally perceived as solely a surveillance mechanism preventing expression of potentially detrimental proteins, is now emerging as a highly regulated RNA decay pathway also acting on a subset of normal mRNAs. We further show that CARM1 associates with major NMD factor UPF1 and promotes its occupancy on PTC-containing transcripts. Finally, we identify a specific subset of NMD targets that are dependent on CARM1 for degradation and that are also misregulated in SMA, potentially adding exacerbated targeting of PTC-containing mRNAs to the already complex array of molecular defects associated with this disease. |
| Databáze: | OpenAIRE |
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