H/ACA Small RNA Dysfunctions in Disease Reveal Key Roles for Noncoding RNA Modifications in Hematopoietic Stem Cell Differentiation

• Published in: Cell reports (Cambridge) Vol. 3; no. 5; pp. 1493 - 1502
• Main Authors: Bellodi, Cristian, McMahon, Mary, Contreras, Adrian, Juliano, Dayle, Kopmar, Noam, Nakamura, Tomoka, Maltby, David, Burlingame, Alma, Savage, Sharon A., Shimamura, Akiko, Ruggero, Davide
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.05.2013; Elsevier
• Subjects: Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation; Differentiation; Dyskeratosis Congenita - genetics; Dyskeratosis Congenita - metabolism; Dyskeratosis Congenita - pathology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ribonucleoproteins, Small Nucleolar - genetics; Ribonucleoproteins, Small Nucleolar - metabolism; RNA, Ribosomal - metabolism; RNA, Untranslated - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.04.030

Noncoding RNAs control critical cellular processes, although their contribution to disease remains largely unexplored. Dyskerin associates with hundreds of H/ACA small RNAs to generate a multitude of functionally distinct ribonucleoproteins (RNPs). The DKC1 gene, encoding dyskerin, is mutated in the multisystem disorder X-linked dyskeratosis congenita (X-DC). A central question is whether DKC1 mutations affect the stability of H/ACA RNPs, including those modifying ribosomal RNA (rRNA). We carried out comprehensive profiling of dyskerin-associated H/ACA RNPs, revealing remarkable heterogeneity in the expression and function of subsets of H/ACA small RNAs in X-DC patient cells. Using a mass spectrometry approach, we uncovered single-nucleotide perturbations in dyskerin-guided rRNA modifications, providing functional readouts of small RNA dysfunction in X-DC. In addition, we identified that, strikingly, the catalytic activity of dyskerin is required for accurate hematopoietic stem cell differentiation. Altogether, these findings reveal that small noncoding RNA dysfunctions may contribute to the pleiotropic manifestation of human disease. [Display omitted] •X-linked dyskeratosis congenita patients have H/ACA small RNA defects•DKC1 mutations lead to impaired H/ACA small-RNA-guided rRNA pseudouridylation•Dyskerin’s pseudouridine synthase activity affects hematopoietic stem cell differentiation The role of noncoding H/ACA small RNAs in disease remains poorly understood. In this study, Ruggero and colleagues identify perturbations in the expression and function of distinct subsets of H/ACA small RNAs in an inherited bone marrow failure disorder, X-DC. Importantly, the authors demonstrate that the catalytic activity of H/ACA small RNP complexes, required for RNA pseudouridine modifications, is important for hematopoietic stem cell differentiation. This study highlights a critical role for H/ACA small RNAs in stem cell function and disease.