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TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo

Lu Chen, Caitlin M. Roake, Paolo Maccallini, Francesca Bavasso, Roozbeh Dehghannasiri, Pamela Santonicola, Natalia Mendoza-Ferreira, Livia Scatolini, Ludovico Rizzuti, Alessandro Esposito, Ivan Gallotta, Sofia Francia, Stefano Cacchione, Matthias Hammerschmidt, Cristiano De Pittà, Gabriele Sales, Julia Salzman, Livio Pellizzoni, Brunhilde Wirth, Elia Di Schiavi, Maurizio Gatti, Steven E. Artandi, Grazia D. Raffa
doi: https://doi.org/10.1101/2020.10.27.356782
Lu Chen
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA
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Caitlin M. Roake
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA
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Paolo Maccallini
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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Francesca Bavasso
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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Roozbeh Dehghannasiri
3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA
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Pamela Santonicola
5Institute of Biosciences and BioResources, IBBR, CNR, Naples, Italy
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Natalia Mendoza-Ferreira
6Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, Univ. of Cologne, 50931 Cologne, Germany
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Livia Scatolini
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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Ludovico Rizzuti
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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Alessandro Esposito
7Institute of Genetics and Biophysics, IGB-ABT, CNR, Naples, Italy
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Ivan Gallotta
7Institute of Genetics and Biophysics, IGB-ABT, CNR, Naples, Italy
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Sofia Francia
8IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
9Istituto di Genetica Molecolare, CNR-Consiglio Nazionale delle Ricerche, Pavia, Italy
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Stefano Cacchione
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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Matthias Hammerschmidt
10Institute for Zoology, Developmental Biology, University of Cologne, 50674 Cologne, Germany
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Cristiano De Pittà
11Department of Biology, University of Padova, Padua, Italy
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Gabriele Sales
11Department of Biology, University of Padova, Padua, Italy
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Julia Salzman
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA
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Livio Pellizzoni
12Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
13Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
14Department of Neurology, Columbia University, New York, NY 10032, USA
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Brunhilde Wirth
6Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, Univ. of Cologne, 50931 Cologne, Germany
15Center for Rare Diseases, University Hospital of Cologne, Univ. of Cologne, 50931 Cologne, Germany
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Elia Di Schiavi
5Institute of Biosciences and BioResources, IBBR, CNR, Naples, Italy
7Institute of Genetics and Biophysics, IGB-ABT, CNR, Naples, Italy
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Maurizio Gatti
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
16Istituto di Biologia e Patologia Molecolari (IBPM) del CNR, Rome, IT
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Steven E. Artandi
1Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
3Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • For correspondence: sartandi@stanford.edu graziadaniela.raffa@uniroma1.it
Grazia D. Raffa
4Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, IT
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  • For correspondence: sartandi@stanford.edu graziadaniela.raffa@uniroma1.it
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ABSTRACT

Trimethylguanosine synthase 1 (TGS1) is a highly conserved enzyme that converts the 5’ mono-methylguanosine cap of snRNAs to a trimethylguanosine cap. Here, we show that loss of TGS1 in C. elegans, D. melanogaster and D. 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 has the ability to 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. Together, these results identify a neuroprotective function for TGS1, reinforcing the view that defects in snRNA maturation negatively affect neuronal viability and function.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵17 Lead Contact

  • https://figshare.com/s/13572f55424106336cac

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TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo
Lu Chen, Caitlin M. Roake, Paolo Maccallini, Francesca Bavasso, Roozbeh Dehghannasiri, Pamela Santonicola, Natalia Mendoza-Ferreira, Livia Scatolini, Ludovico Rizzuti, Alessandro Esposito, Ivan Gallotta, Sofia Francia, Stefano Cacchione, Matthias Hammerschmidt, Cristiano De Pittà, Gabriele Sales, Julia Salzman, Livio Pellizzoni, Brunhilde Wirth, Elia Di Schiavi, Maurizio Gatti, Steven E. Artandi, Grazia D. Raffa
bioRxiv 2020.10.27.356782; doi: https://doi.org/10.1101/2020.10.27.356782
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TGS1 controls snRNA 3’ end processing, prevents neurodegeneration and ameliorates SMN-dependent neurological phenotypes in vivo
Lu Chen, Caitlin M. Roake, Paolo Maccallini, Francesca Bavasso, Roozbeh Dehghannasiri, Pamela Santonicola, Natalia Mendoza-Ferreira, Livia Scatolini, Ludovico Rizzuti, Alessandro Esposito, Ivan Gallotta, Sofia Francia, Stefano Cacchione, Matthias Hammerschmidt, Cristiano De Pittà, Gabriele Sales, Julia Salzman, Livio Pellizzoni, Brunhilde Wirth, Elia Di Schiavi, Maurizio Gatti, Steven E. Artandi, Grazia D. Raffa
bioRxiv 2020.10.27.356782; doi: https://doi.org/10.1101/2020.10.27.356782

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