Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan

Abstract

Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

“…m 5 C modifications can be installed by any of the seven proteins of the Nol1/Nop2/SUN domain (NSUN) family and by an enzyme named DNA methyltransferase 2 (DNMT2). DNMT2 mainly catalyses the m 5 C modification in position 38 of tRNA Asp in human cells (Goll et al , 2006), while the so far characterised NSUN proteins show specificity for tRNAs (NSUN2, NSUN6; Schaefer et al , 2010; Tuorto et al , 2012; Blanco et al , 2014; Haag et al , 2015a) or rRNA (NSUN1/NOP2, NSUN5; Sloan et al , 2013; Tafforeau et al , 2013; Schosserer et al , 2015). NSUN2 can also modify vault RNAs and mRNAs (Hussain et al , 2013), and NSUN4 was described to localise to mitochondria where it was shown to methylate the mitochondrial 12S rRNA in mice (Cámara et al , 2011; Metodiev et al , 2014).…”

Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs

“…In this context, it has been shown that m5C modification of tRNA plays an important role in tRNA stability and in the regulation of translational fidelity (Schaefer et al 2010;Tuorto et al 2012Tuorto et al , 2015. Furthermore, m5C is also a widely conserved modification of rRNA, where it is implied in the quality control of ribosome biogenesis (Sharma et al 2013;Bourgeois et al 2015;Schosserer et al 2015). These processes have been associated with a variety of human diseases (Blanco and Frye 2014).…”

NSUN6 is a human RNA methyltransferase that catalyzes formation of m5C72 in specific tRNAs

“…Although the target spectrum of these family members is less well studied, the yeast homologs of NSUN1 and NSUN5, Nop2 and Rcm1, have been shown to methylate residues in the 28S ribosomal RNA at positions C2870 and C2278, respectively . In humans, knockdown of NSUN1 causes severe pre-rRNA processing defects, whereas depletion of NSUN5 leads to only mild defects in the biogenesis of the large ribosomal subunit (Sloan et al 2013;Tafforeau et al 2013;Schosserer et al 2015). Another member of the NSUN family, NSUN4 was recently found to localize to mitochondria and to methylate C911 in the mitochondrial 12S rRNA in mice (Metodiev et al 2014).…”