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

作者：Moore Joseph B; Farrar Jason E; Arceci Robert J; Liu Johnson M; Ellis Steven R^*

来源：Haematologica-The Hematology Journal, 2010, 95(1): 57-64.

DOI：10.3324/haematol.2009.012450

• bone marrow failure syndrome
• abortive ribosome assembly
• signaling pathways
• half-mer polysomes

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 Shwactiman-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.

• 出版日期2010-1
• 单位河北医科大学