Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth

Nucleic Acids Res. 2019 Dec 16;47(22):11807-11825. doi: 10.1093/nar/gkz1043.

Clemens Heissenberger ¹, Lisa Liendl ¹, Fabian Nagelreiter ¹, Yulia Gonskikh ², Guohuan Yang ³, Elena M Stelzer ¹, Teresa L Krammer ¹, Lucia Micutkova ⁴, Stefan Vogt ¹, David P Kreil ¹, Gerhard Sekot ¹, Emilio Siena ¹, Ina Poser ⁵, Eva Harreither ¹, Angela Linder ¹, Viktoria Ehret ⁶, Thomas H Helbich ⁶, Regina Grillari-Voglauer ¹, Pidder Jansen-Dürr ⁴, Martin Koš ³, Norbert Polacek ², Johannes Grillari ¹ ⁷ ⁸, Markus Schosserer ¹

Affiliations

1 Department of Biotechnology, Institute of Molecular Biotechnology, University of Natural Resources and Life Sciences, Vienna, 1190 Vienna, Austria.
2 Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
3 Biochemistry Center, University of Heidelberg, 69120 Heidelberg, Germany.
4 Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
5 Max Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
6 Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Preclinical Imaging Laboratory, Medical University of Vienna, 1090 Vienna, Austria.
7 Christian Doppler Laboratory on Biotechnology of Skin Aging, 1190 Vienna, Austria.
8 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria.

PMID: 31722427 DOI: 10.1093/nar/gkz1043

Abstract

Modifications of ribosomal RNA expand the nucleotide repertoire and thereby contribute to ribosome heterogeneity and translational regulation of gene expression. One particular m5C modification of 25S ribosomal RNA, which is introduced by Rcm1p, was previously shown to modulate stress responses and lifespan in yeast and Other small organisms. Here, we report that NSUN5 is the functional orthologue of Rcm1p, introducing m5C3782 into human and m5C3438 into mouse 28S ribosomal RNA. Haploinsufficiency of the NSUN5 gene in fibroblasts from William Beuren syndrome patients causes partial loss of this modification. The N-terminal domain of NSUN5 is required for targeting to nucleoli, while two evolutionary highly conserved cysteines mediate catalysis. Phenotypic consequences of NSUN5 deficiency in mammalian cells include decreased proliferation and size, which can be attributed to a reduction in total protein synthesis by altered ribosomes. Strikingly, Nsun5 knockout in mice causes decreased body weight and lean mass without alterations in food intake, as well as a trend towards reduced protein synthesis in several tissues. Together, our findings emphasize the importance of single RNA modifications for ribosome function and normal cellular and organismal physiology.

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