Journal
CELL REPORTS
Volume 3, Issue 5, Pages 1493-1502Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.04.030
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Funding
- intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- NIH NIGMS [8P41GM103481]
- Howard Hughes Medical Institute [NIH R01DK098057, NIH R01HL085572, NIH 3R01HL085572-05S1]
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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.
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