biostudies-literatureUnknownChen LGerman Research FoundationItalian Ministry of HealthMSTPAIRCH2020NIHFondazione CariploEuropean Research CouncilTelethonStanford Cancer InstituteMarie Skłodowska-CurieNINDS NIH HHSItalian Ministry of Economy and FinanceNIH HHSMinistry of Economy and FinanceTrimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5'-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.Nucleic acids researchgkac659https://www.ebi.ac.uk/biostudies/studies/S-EPMC9757054biostudies-literatureTGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration.PMC9757054IASIS_727658ASTRA_8559232014-1215Wi 945/17-1727658INFORE_825080IG 26496R01 NS102451855923RIBOMYLOME_309545NS102451IG 20528AG056575GM007365956185309545GGP16203RF 2009-1473235GPP13147CA197563Roake CMPellizzoni LMaccallini PRizzuti LBavasso FScatolini LGalati AKobin MADe Pitta CArtandi SEGallotta IWu YSales GDi Schiavi EEsposito ACacchione SGatti MChen LFrancia SHammerschmidt MProietti GTartaglia GGWirth BSantonicola PColantoni ASalzman JMendoza-Ferreira NPalumbo VDehghannasiri RRaffa GDfalseTGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration.Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5'-monomethylguanosine cap of small nuclear RNAs (snRNAs) to a trimethylguanosine cap. Here, we show that loss of TGS1 in Caenorhabditis elegans, Drosophila melanogaster and Danio rerio results in neurological phenotypes similar to those caused by survival motor neuron (SMN) deficiency. Importantly, expression of human TGS1 ameliorates the SMN-dependent neurological phenotypes in both flies and worms, revealing that TGS1 can partly counteract the effects of SMN deficiency. TGS1 loss in HeLa cells leads to the accumulation of immature U2 and U4atac snRNAs with long 3' tails that are often uridylated. snRNAs with defective 3' terminations also accumulate in Drosophila Tgs1 mutants. Consistent with defective snRNA maturation, TGS1 and SMN mutant cells also exhibit partially overlapping transcriptome alterations that include aberrantly spliced and readthrough transcripts. Together, these results identify a neuroprotective function for TGS1 and reinforce the view that defective snRNA maturation affects neuronal viability and function.2022-01-01T00:00:00Z2022 Aug2024-11-20T16:09:19.068Z2024-11-20T16:09:19.068ZS-EPMC97570543594765010.1093/nar/gkac659