BMSEHA15
Published online 27 August 2009
Haematologica, Vol 95, Issue 1, 57-64 doi:10.3324/haematol.2009.012450
Copyright © 2010 by Ferrata Storti Foundation
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moore, J. B.
Right arrow Articles by Ellis, S. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moore, J. B., IV
Right arrow Articles by Ellis, S. R.

Bone Marrow Failure

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

Joseph B. Moore, IV1, Jason E. Farrar2, Robert J. Arceci2, Johnson M. Liu3, Steven R. Ellis1

1 Department of Biochemistry and Molecular Biology, University of Louisville, Louisville
2 Division of Pediatric Oncology, Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
3 The Feinstein Institute for Medical Research, Manhasset, Schneider Children’s Hospital, NY, USA

Correspondence: Steven R. Ellis, Department of Biochemistry, and Molecular Biology, University of Louisville, Louisville, Kentucky, 40292 USA. E-mail: srellis{at}louisville.edu

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.

Key words: bone marrow failure syndrome, abortive ribosome assembly, signaling pathways, half-mer polysomes.