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

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.

Pubmed ID: 22099312

Authors

  • Jack K
  • Bellodi C
  • Landry DM
  • Niederer RO
  • Meskauskas A
  • Musalgaonkar S
  • Kopmar N
  • Krasnykh O
  • Dean AM
  • Thompson SR
  • Ruggero D
  • Dinman JD

Journal

Molecular cell

Publication Data

November 18, 2011

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 3R01GM058859-10A1S1
  • Agency: NIGMS NIH HHS, Id: 3R01GM084547-01A1S1
  • Agency: NHLBI NIH HHS, Id: 3R01HL085572-05S1
  • Agency: NIGMS NIH HHS, Id: 5R01GM058859
  • Agency: NIGMS NIH HHS, Id: R01 GM058859
  • Agency: NIGMS NIH HHS, Id: R01 GM058859-10A1
  • Agency: NIGMS NIH HHS, Id: R01 GM058859-10A1S1
  • Agency: NIGMS NIH HHS, Id: R01 GM058859-11
  • Agency: NIGMS NIH HHS, Id: R01 GM058859-12
  • Agency: NIGMS NIH HHS, Id: R01 GM058859-13
  • Agency: NIGMS NIH HHS, Id: R01 GM084547
  • Agency: NIGMS NIH HHS, Id: R01 GM084547-01A1S1
  • Agency: NIGMS NIH HHS, Id: R01 GM084547-02
  • Agency: NIGMS NIH HHS, Id: R01 GM084547-03
  • Agency: NIGMS NIH HHS, Id: R01 GM084547-04
  • Agency: NHLBI NIH HHS, Id: R01 HL085572
  • Agency: NHLBI NIH HHS, Id: R01 HL085572-03
  • Agency: NHLBI NIH HHS, Id: R01 HL085572-04
  • Agency: NHLBI NIH HHS, Id: R01 HL085572-05
  • Agency: NHLBI NIH HHS, Id: R01 HL085572-05S1
  • Agency: NIGMS NIH HHS, Id: R01GM084547
  • Agency: NHLBI NIH HHS, Id: R01HL085572

Mesh Terms

  • 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