Distinct ribosome maturation defects in yeast models of Diamond-Blackfan anemia and Shwachman-Diamond syndrome

Joseph B. Moore IV, Jason E. Farrar, Robert J. Arceci, Johnson M. Liu, Steven R. Ellis

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Diamond-Blackfan anemia and Shwachman-Diamond syndrome are inherited bone marrow failure syndromes linked to defects in ribosome synthesis. The purpose of this study was to determine whether yeast models for Diamond-Blackfan anemia and Shwachman-Diamond syndrome differed in the mechanism by which ribosome synthesis was affected. Design and Methods: Northern blotting, pulse-chase analysis, and polysome profiling were used to study ribosome synthesis in yeast models. Localization of 60S ribosomal subunits was assessed using RPL25eGFP. Results: Relative to wild-type controls, each disease model showed defects in 60S subunit maturation, but with distinct underlying mechanisms. In the model of Diamond-Blackfan anemia, 60S subunit maturation was disrupted at a relatively early stage with abortive complexes subject to rapid degradation. 5S ribosomal RNA, unlike other large subunit ribosomal RNA in this model, accumulated as an extra-ribosomal species. In contrast, subunit maturation in the Shwachman-Diamond syndrome model was affected at a later step, giving rise to relatively stable pre-60S particles with associated 5S ribosomal RNA retained in the nucleus. Conclusions: These differences between the yeast Diamond-Blackfan anemia and Shwachman-Diamond syndrome models have implications for signaling mechanisms linking abortive ribosome assembly to cell fate decisions and may contribute to the divergent clinical presentations of Diamond-Blackfan anemia and Shwachman-Diamond syndrome.

Original languageEnglish (US)
Pages (from-to)57-64
Number of pages8
JournalHaematologica
Volume95
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Keywords

  • Abortive ribosome assembly
  • Bone marrow failure syndrome
  • Half-mer polysomes
  • Signaling pathways

ASJC Scopus subject areas

  • Hematology

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