title: H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation.
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.
authors.affiliation: School of Medicine and Department of Urology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA 94115, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bellodi
authors.forename: Mary
authors.initials: M
authors.lastname: McMahon
authors.forename: Adrian
authors.initials: A
authors.lastname: Contreras
authors.forename: Dayle
authors.initials: D
authors.lastname: Juliano
authors.forename: Noam
authors.initials: N
authors.lastname: Kopmar
authors.forename: Tomoka
authors.initials: T
authors.lastname: Nakamura
authors.forename: David
authors.initials: D
authors.lastname: Maltby
authors.forename: Alma
authors.initials: A
authors.lastname: Burlingame
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019871:Dyskeratosis Congenita / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism*; D020718:Ribonucleoproteins, Small Nucleolar / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; C485802:GAR1 protein, human; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D022661:RNA, Untranslated; D020718:Ribonucleoproteins, Small Nucleolar