title: Distinct ribosome maturation defects in yeast models of Diamond-Blackfan anemia and Shwachman-Diamond syndrome.
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.
  
  
  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.
authors.affiliation: Department of Biochemistry, and Molecular Biology, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moore
authors.forename: Jason E
authors.initials: JE
authors.lastname: Farrar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Johnson M
authors.initials: JM
authors.lastname: Liu
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D012269:Ribosomal Proteins / Q000235:genetics; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics; D012270:Ribosomes / Q000235:genetics* / Q000473:pathology; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C027624:ribosomal protein L11; C031127:ribosomal protein L25; C549166:ribosomal protein L5, human