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.

Diverse role of survival motor neuron protein

“…Consistently, CARM1 is upregulated in tissues from SMA mouse models as well as in SMA type I patient cells [121]. Increased expression of CARM1 has been shown to cause an aberrant increase in inclusion of exon 2 of the Ubiquitin-Specific Protease-Like 1 ( USPL1 ) gene that codes for a SUMO isopeptidase [122]. The exon 2-containing transcript of USPL1 is also upregulated in mouse models of SMA as well as in SMA type I patient cells [122,141,142,200].…”

“…SMN controls various aspects of the RNA metabolism, including but not limited to transcription [90], pre-mRNA splicing [106], snRNP assembly [20,72,108–115], the 3′ end of histone mRNA processing [116,117], snoRNP assembly [82,118,119], telomerase activity [119], SG formation [120], translation [121,122], signal recognition particle (SRP) biogenesis [123] and mRNA trafficking [124–130] (Fig. 3).…”

“…It has been argued that the splicing of minor introns in particular is affected in SMA [146]. There is evidence to suggest that some of the effects on alternative splicing are indirect, since levels of factors that are involved in splicing could also be affected by downregulation of SMN [122]. Overall, the mechanism by which SMN deficiency triggers aberrant splicing of specific introns remains to be understood.…”

“…CARM1 is a multifunctional protein that affects transcription, splicing and autophagy [122,197–199]. Downregulation of SMN increases the level of CARM1 [122]. Consistently, CARM1 is upregulated in tissues from SMA mouse models as well as in SMA type I patient cells [121].…”

“…Increased expression of CARM1 has been shown to cause an aberrant increase in inclusion of exon 2 of the Ubiquitin-Specific Protease-Like 1 ( USPL1 ) gene that codes for a SUMO isopeptidase [122]. The exon 2-containing transcript of USPL1 is also upregulated in mouse models of SMA as well as in SMA type I patient cells [122,141,142,200]. These findings support a point of view that the aberrant splicing of USPL1 exon 2 in SMA is the consequence of upregulation of CARM1.…”