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

Bellodi, Cristian LU ; McMahon, Mary; Contreras, Adrian; Juliano, Dayle; Kopmar, Noam; Nakamura, Tomoka; Maltby, David; Burlingame, Alma; Savage, Sharon A and Shimamura, Akiko, et al. (2013) In Cell Reports 3(5). p.502-1493
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... (More)

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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publication status
published
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keywords
Cell Cycle Proteins, Cell Differentiation, Dyskeratosis Congenita, Hematopoietic Stem Cells, Humans, Mutation, Nuclear Proteins, RNA, Ribosomal, RNA, Untranslated, Ribonucleoproteins, Small Nucleolar
in
Cell Reports
volume
3
issue
5
pages
10 pages
publisher
Cell Press
external identifiers
  • Scopus:84878596830
ISSN
2211-1247
DOI
10.1016/j.celrep.2013.04.030
language
English
LU publication?
no
id
fe4ea74f-e20f-4d94-8ed7-e2c10679e41d
date added to LUP
2016-04-29 15:41:53
date last changed
2016-11-27 04:39:51
@misc{fe4ea74f-e20f-4d94-8ed7-e2c10679e41d,
  abstract     = {<p>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.</p>},
  author       = {Bellodi, Cristian and McMahon, Mary and Contreras, Adrian and Juliano, Dayle and Kopmar, Noam and Nakamura, Tomoka and Maltby, David and Burlingame, Alma and Savage, Sharon A and Shimamura, Akiko and Ruggero, Davide},
  issn         = {2211-1247},
  keyword      = {Cell Cycle Proteins,Cell Differentiation,Dyskeratosis Congenita,Hematopoietic Stem Cells,Humans,Mutation,Nuclear Proteins,RNA, Ribosomal,RNA, Untranslated,Ribonucleoproteins, Small Nucleolar},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {502--1493},
  publisher    = {ARRAY(0x8709c90)},
  series       = {Cell Reports},
  title        = {H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation},
  url          = {http://dx.doi.org/10.1016/j.celrep.2013.04.030},
  volume       = {3},
  year         = {2013},
}