title: Severity of X-linked dyskeratosis congenita (DKCX) cellular defects is not directly related to dyskerin (DKC1) activity in ribosomal RNA biogenesis or mRNA translation.
abstract: Dyskerin (encoded by the DKC1 locus) is the pseudouridine synthase responsible for the modification of noncoding RNA. Dyskerin is also an obligate member of the telomerase enzyme, and participates in the biogenesis of telomerase. Genetic lesions at the DKC1 locus are associated with X-linked dyskeratosis congenita (X-DC) and the Hoyeraal-Hreidarsson Syndrome (HHS). Both syndromes have been linked to deficient telomere maintenance, but little is known about the RNA modification activities of dyskerin in X-DC and HHS cells. To evaluate whether X-DC-associated dyskerin mutations affect the modification or function of ribosomal RNA, we studied five telomerase-rescued X-DC cells (X-DC(T) ). Our data revealed a small reproducible loss of pseudouridines in mature rRNA in two X-DC variants. However, we found no difference in protein synthesis between telomerized wild-type (WT(T) ) and X-DC(T) cells, with an internal ribosomal entry site translation assay, or by measuring total protein synthesis in live cells. X-DC(T) cells and WT(T) cells also exhibited similar tolerances to ionizing radiation and endoplasmic reticulum stress. Despite the loss in rRNA pseudouridine modification, functional perturbations from these changes are secondary to the telomere maintenance defects of X-DC. Our data show that telomere dysfunction is the primary and unifying etiology of X-DC.
authors.affiliation: Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Naresh R
authors.initials: NR
authors.lastname: Thumati
authors.forename: Xi-Lei
authors.initials: XL
authors.lastname: Zeng
authors.forename: Hilda H T
authors.initials: HH
authors.lastname: Au
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jang
authors.forename: Eric
authors.initials: E
authors.lastname: Jan
authors.forename: Judy M Y
authors.initials: JM
authors.lastname: Wong
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D014176:Protein Biosynthesis; D012335:RNA, Ribosomal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D054657:Ribosome Subunits / Q000378:metabolism; D012720:Severity of Illness Index; D013312:Stress, Physiological; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D011994:Recombinant Proteins; D019098:Telomerase
keywords: DKC1; X-linked dyskeratosis congenita; dyskerin; ribosomal RNA; ribosomes