Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond-Blackfan Anemia.

Abstract

Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to "ribosomal stress" with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.

• Authors: Anna Aspesi, Elisa Pavesi, Elisa Robotti, Rossella Crescitelli, Ilenia Boria, Federica Avondo, Hélène Moniz, Lydie Da Costa, Narla Mohandas, Paola Roncaglia, Ugo Ramenghi, Antonella Ronchi, Stefano Gustincich, Simone Merlin, Emilio Marengo, Steven R Ellis, Antonia Follenzi, Claudio Santoro, Irma Dianzani
• Journal: Gene (Gene) Vol. 545 Issue 2 Pg. 282-9 (Jul 25 2014) ISSN: 1879-0038 [Electronic] Netherlands
• PMID: 24835311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier B.V.

Chemical References

• Ribosomal Proteins
• Tumor Suppressor Protein p53
• ribosomal protein S19

Topics

• Alternative Splicing
• Anemia, Diamond-Blackfan (genetics, metabolism)
• Cell Line
• DNA Mutational Analysis
• Gene Expression Regulation
• Gene Order
• Humans
• Molecular Sequence Annotation
• Mutation
• Phenotype
• Reproducibility of Results
• Ribosomal Proteins (deficiency, genetics, metabolism)
• Transcription, Genetic
• Transcriptome
• Tumor Suppressor Protein p53 (genetics, metabolism)