title: Effects of dyskeratosis congenita mutations in dyskerin, NHP2 and NOP10 on assembly of H/ACA pre-RNPs.
abstract: Dyskeratosis congenita (DC) is a rare genetic syndrome that gives rise to a variety of disorders in affected individuals. Remarkably, all causative gene mutations identified to date share a link to telomere/telomerase biology. We found that the most prevalent dyskerin mutation in DC (A353V) did not affect formation of the NAF1-dyskerin-NOP10-NHP2 tetramer that normally assembles with nascent H/ACA RNAs in vivo. However, the A353V mutation slightly reduced pre-RNP assembly with the H/ACA-like domain of human telomerase RNA (hTR). In contrast, NHP2 mutations V126M and Y139H impaired association with NOP10, leading to major pre-RNP assembly defects with all H/ACA RNAs tested, including the H/ACA domain of hTR. Mutation R34W in NOP10 caused no apparent defect in protein tetramer formation, but it severely affected pre-RNP assembly with the H/ACA domain of hTR and a subset of H/ACA RNAs. Surprisingly, H/ACA sno/scaRNAs that encode miRNAs were not affected by the mutation R34W, and they were able to form pre-RNPs with NOP10-R34W. This indicates structural differences between H/ACA RNPs that encode miRNAs and those that do not. Altogether, our results suggest that, in addition to major defects in the telomere/telomerase pathways, some of the disorders occurring in DC may be caused by alteration of most H/ACA RNPs, or by only a subset of them.
authors.affiliation: Département des sciences biologiques and Centre de recherche BioMed, Université du Québec à Montréal, Montréal, QC, Canada H3C 3P8,
authors.forename: Christian
authors.initials: C
authors.lastname: Trahan
authors.forename: Caroline
authors.initials: C
authors.lastname: Martel
authors.forename: François
authors.initials: F
authors.lastname: Dragon
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D019871:Dyskeratosis Congenita / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics* / Q000378:metabolism; D020718:Ribonucleoproteins, Small Nucleolar / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; C485802:GAR1 protein, human; D035683:MicroRNAs; C416929:NHP2 protein, human; C416930:NOP10 protein, human; D009687:Nuclear Proteins; D017411:Ribonucleoproteins, Small Nuclear; D020718:Ribonucleoproteins, Small Nucleolar