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PMID: 23707062 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation.

Cell reports ·Vol. 3 ·No. 5 ·2013-05-30 ·Pages 1493-502

Bellodi C, McMahon M, Contreras A, Juliano D, Kopmar N, Nakamura T, Maltby D, Burlingame A, Savage SA, Shimamura A, Ruggero D

Abstract

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.

MeSH Terms
Cell Cycle Proteins/genetics,metabolism Cell Differentiation Dyskeratosis Congenita/genetics,metabolism,pathology Hematopoietic Stem Cells/cytology,metabolism Humans Mutation Nuclear Proteins/genetics,metabolism RNA, Ribosomal/metabolism RNA, Untranslated/metabolism Ribonucleoproteins, Small Nucleolar/genetics,metabolism
Chemicals
Cell Cycle Proteins DKC1 protein, human GAR1 protein, human Nuclear Proteins RNA, Ribosomal RNA, Untranslated Ribonucleoproteins, Small Nucleolar
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Bellodi Cristian
School of Medicine and Department of Urology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA 94115, USA.
McMahon Mary
Contreras Adrian
Juliano Dayle
Kopmar Noam
Nakamura Tomoka
Maltby David
Burlingame Alma
Savage Sharon A
Shimamura Akiko
Ruggero Davide
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Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2013.04.030
Published
2013-05-30
Epub
2013-00-23
Pages
1493-502
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC3857015
Subset
IM
Grants
NHLBI NIH HHS · R01 HL085572 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · 3R01HL085572-05S1 · United States
NHLBI NIH HHS · R01HL085572 · United States
Intramural NIH HHS · United States
NIDDK NIH HHS · R01 DK098057 · United States
NIDDK NIH HHS · R01DK098057 · United States
NIGMS NIH HHS · P41 GM103481 · United States
NIGMS NIH HHS · 8P41GM103481 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2013.04.030 PMC Full Text View journal details
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