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rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells

Jack, Karen ; Bellodi, Cristian LU ; Landry, Dori M ; Niederer, Rachel O ; Meskauskas, Arturas ; Musalgaonkar, Sharmishtha ; Kopmar, Noam ; Krasnykh, Olya ; Dean, Alison M and Thompson, Sunnie R , et al. (2011) In Molecular Cell 44(4). p.6-660
Abstract

How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome... (More)

How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Ψ modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans.

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publication status
published
subject
keywords
Animals, Binding Sites, Cell Cycle Proteins, Dyskeratosis Congenita, Fetal Growth Retardation, Genes, Reporter, Humans, Hydro-Lyases, Intellectual Disability, Luciferases, Mice, Microcephaly, Microtubule-Associated Proteins, Mutation, Nuclear Proteins, Plasmids, Protein Biosynthesis, RNA, Ribosomal, RNA, Transfer, Ribonucleoproteins, Small Nuclear, Ribosomes, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Transduction, Genetic
in
Molecular Cell
volume
44
issue
4
pages
7 pages
publisher
Cell Press
external identifiers
  • pmid:22099312
  • scopus:81355153985
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.09.017
language
English
LU publication?
no
id
21155f13-a460-4755-bb6d-7925968b8683
date added to LUP
2016-04-29 15:46:30
date last changed
2024-04-18 22:19:03
@article{21155f13-a460-4755-bb6d-7925968b8683,
  abstract     = {{<p>How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Ψ modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans.</p>}},
  author       = {{Jack, Karen and Bellodi, Cristian and Landry, Dori M and Niederer, Rachel O and Meskauskas, Arturas and Musalgaonkar, Sharmishtha and Kopmar, Noam and Krasnykh, Olya and Dean, Alison M and Thompson, Sunnie R and Ruggero, Davide and Dinman, Jonathan D}},
  issn         = {{1097-4164}},
  keywords     = {{Animals; Binding Sites; Cell Cycle Proteins; Dyskeratosis Congenita; Fetal Growth Retardation; Genes, Reporter; Humans; Hydro-Lyases; Intellectual Disability; Luciferases; Mice; Microcephaly; Microtubule-Associated Proteins; Mutation; Nuclear Proteins; Plasmids; Protein Biosynthesis; RNA, Ribosomal; RNA, Transfer; Ribonucleoproteins, Small Nuclear; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; Transduction, Genetic}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{4}},
  pages        = {{6--660}},
  publisher    = {{Cell Press}},
  series       = {{Molecular Cell}},
  title        = {{rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells}},
  url          = {{http://dx.doi.org/10.1016/j.molcel.2011.09.017}},
  doi          = {{10.1016/j.molcel.2011.09.017}},
  volume       = {{44}},
  year         = {{2011}},
}