RRC ID 28736
Author Wong CC, Traynor D, Basse N, Kay RR, Warren AJ.
Title Defective ribosome assembly in Shwachman-Diamond syndrome.
Journal Blood
Abstract Shwachman-Diamond syndrome (SDS), a recessive leukemia predisposition disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, skeletal abnormalities and poor growth, is caused by mutations in the highly conserved SBDS gene. Here, we test the hypothesis that defective ribosome biogenesis underlies the pathogenesis of SDS. We create conditional mutants in the essential SBDS ortholog of the ancient eukaryote Dictyostelium discoideum using temperature-sensitive, self-splicing inteins, showing that mutant cells fail to grow at the restrictive temperature because ribosomal subunit joining is markedly impaired. Remarkably, wild type human SBDS complements the growth and ribosome assembly defects in mutant Dictyostelium cells, but disease-associated human SBDS variants are defective. SBDS directly interacts with the GTPase elongation factor-like 1 (EFL1) on nascent 60S subunits in vivo and together they catalyze eviction of the ribosome antiassociation factor eukaryotic initiation factor 6 (eIF6), a prerequisite for the translational activation of ribosomes. Importantly, lymphoblasts from SDS patients harbor a striking defect in ribosomal subunit joining whose magnitude is inversely proportional to the level of SBDS protein. These findings in Dictyostelium and SDS patient cells provide compelling support for the hypothesis that SDS is a ribosomopathy caused by corruption of an essential cytoplasmic step in 60S subunit maturation.
Volume 118(16)
Pages 4305-12
Published 2011-10-20
DOI 10.1182/blood-2011-06-353938
PII blood-2011-06-353938
PMID 21803848
MeSH Bone Marrow Diseases / genetics* Bone Marrow Diseases / metabolism Bone Marrow Diseases / pathology* Cell Line Dictyostelium / genetics Dictyostelium / metabolism Exocrine Pancreatic Insufficiency / genetics* Exocrine Pancreatic Insufficiency / metabolism Exocrine Pancreatic Insufficiency / pathology* GTP Phosphohydrolases / metabolism Humans Lipomatosis / genetics* Lipomatosis / metabolism Lipomatosis / pathology* Mutation Peptide Initiation Factors / metabolism Proteins / genetics* Proteins / metabolism Protozoan Proteins / genetics Protozoan Proteins / metabolism Ribosomes / genetics Ribosomes / metabolism Ribosomes / pathology* Shwachman-Diamond Syndrome
IF 16.601
Times Cited 85
WOS Category HEMATOLOGY
Resource
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