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

Schosserer M, Minois N, Angerer TB, Amring M, Dellago H, Harreither E, Calle-Perez A, Pircher A, Gerstl MP, Pfeifenberger S, Brandl C, Sonntagbauer M, Kriegner A, Linder A, Weinhäusel A, Mohr T, Steiger M, Mattanovich D, Rinnerthaler M, Karl T, Sharma S, Entian KD, Kos M, Breitenbach M, Wilson IB, Polacek N, Grillari-Voglauer R, Breitenbach-Koller L, Grillari J - Nat Commun (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria.

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.

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NSUN5 is conserved from yeast to humans.Multiple protein sequence alignment of NSUN5 orthologues from S. cerevisiae, C. elegans, D. melanogaster, mice and humans. Identities are marked with black boxes and functional domains are highlighted.
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f1: NSUN5 is conserved from yeast to humans.Multiple protein sequence alignment of NSUN5 orthologues from S. cerevisiae, C. elegans, D. melanogaster, mice and humans. Identities are marked with black boxes and functional domains are highlighted.

Mentions: To study if NSUN5 is causally involved in the aging process, we tested if its downregulation in yeast, worm and fly would modulate their respective lifespans. Therefore, we identified the previously uncharacterized open reading frames CG42358 (NCBI Unigene accession code NP_650787.1) in Drosophila melanogaster, Y53F4B.4 (NP_497089.2) in Caenorhabditis elegans and YNL022C (NP_014376.3) in S. cerevisiae as the closest sequence homologues to the human protein. An alignment of protein sequences of NSUN5 homologues showed high conservation, especially within the functional domain of an RNA methyltransferase (Fig. 1). We propose using the names NSUN5 (Nop2/Sun-like domain containing protein 5) for the human gene, RCM1 (rRNA cytosine methylase) for the yeast, dNsun5 for the fly, and nsun-5 for the worm homologue.


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

Schosserer M, Minois N, Angerer TB, Amring M, Dellago H, Harreither E, Calle-Perez A, Pircher A, Gerstl MP, Pfeifenberger S, Brandl C, Sonntagbauer M, Kriegner A, Linder A, Weinhäusel A, Mohr T, Steiger M, Mattanovich D, Rinnerthaler M, Karl T, Sharma S, Entian KD, Kos M, Breitenbach M, Wilson IB, Polacek N, Grillari-Voglauer R, Breitenbach-Koller L, Grillari J - Nat Commun (2015)

NSUN5 is conserved from yeast to humans.Multiple protein sequence alignment of NSUN5 orthologues from S. cerevisiae, C. elegans, D. melanogaster, mice and humans. Identities are marked with black boxes and functional domains are highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317494&req=5

f1: NSUN5 is conserved from yeast to humans.Multiple protein sequence alignment of NSUN5 orthologues from S. cerevisiae, C. elegans, D. melanogaster, mice and humans. Identities are marked with black boxes and functional domains are highlighted.
Mentions: To study if NSUN5 is causally involved in the aging process, we tested if its downregulation in yeast, worm and fly would modulate their respective lifespans. Therefore, we identified the previously uncharacterized open reading frames CG42358 (NCBI Unigene accession code NP_650787.1) in Drosophila melanogaster, Y53F4B.4 (NP_497089.2) in Caenorhabditis elegans and YNL022C (NP_014376.3) in S. cerevisiae as the closest sequence homologues to the human protein. An alignment of protein sequences of NSUN5 homologues showed high conservation, especially within the functional domain of an RNA methyltransferase (Fig. 1). We propose using the names NSUN5 (Nop2/Sun-like domain containing protein 5) for the human gene, RCM1 (rRNA cytosine methylase) for the yeast, dNsun5 for the fly, and nsun-5 for the worm homologue.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria.

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.

Show MeSH
Related in: MedlinePlus