title: A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy.
abstract: 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.
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sanchez
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Bondy-Chorney
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Janik
authors.initials: J
authors.lastname: Laframboise
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Paris
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Andréanne
authors.initials: A
authors.lastname: Didillon
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Jasmin
authors.affiliation: Centre for Neuromuscular Disease, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada jcote@uottawa.ca.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Côté
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D018388:Codon, Terminator; D005091:Exons; D006801:Humans; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059365:Nonsense Mediated mRNA Decay; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D020365:RNA Helicases; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; D012333:RNA, Messenger; D015534:Trans-Activators; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D020365:RNA Helicases; C101828:UPF1 protein, human