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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author HeissenbergerClemens, LiendlLisa, NagelreiterFabian, GonskikhYulia, YangGuohuan, StelzerElena, KrammerTeresa, MicutkovaLucia, VogtStefan, KreilDavid, SekotGerhard, SienaEmilio, PoserIna, HarreitherEva, LinderAngela, EhretViktoria, HelbichThomas, Grillari-VoglauerRegina, Jansen-DürrPidder, KosMartin, PolacekNorbert, GrillariJohannes, SchossererMarkus,
Project Stress-mediated effects on ribosome functions and translation control
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Original article (peer-reviewed)

Journal Nucleic Acids Research
Page(s) 1043
Title of proceedings Nucleic Acids Research
DOI 10.1093/nar/gkz1043

Open Access

URL https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz1043/5624972
Type of Open Access Publisher (Gold Open Access)

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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