RRNA Pseudouridylation Defects Affect Ribosomal Ligand Binding and Translational Fidelity from Yeast to Human Cells

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Nov 22

PMID 22099312

Citations 191

Authors

Karen Jack

Cristian Bellodi

Dori M Landry

Rachel O Niederer

Arturas Meskauskas

Sharmishtha Musalgaonkar

Noam Kopmar

Olya Krasnykh

Alison M Dean

Sunnie R Thompson

Davide Ruggero

Jonathan D Dinman

Affiliations

Soon will be listed here.

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 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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