Journal
BLOOD
Volume 118, Issue 16, Pages 4305-4312Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-06-353938
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Funding
- Medical Research Council
- Raymond and Beverly Sackler Fund
- Leukemia and Lymphoma Research
- Association for International Cancer Research
- Sylvia Aitken Trust
- MDS Foundation
- Leukemia & Lymphoma Society of America
- Shwachman-Diamond United Kingdom
- Ted's Gang
- Tesni Parry Memorial Fund
- Cambridge NIHR Biomedical Research Center
- MRC [MC_U105161083, MC_U105115237] Funding Source: UKRI
- Medical Research Council [MC_U105115237, MC_U105161083] Funding Source: researchfish
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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. (Blood. 2011;118(16):4305-4312)
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