Severity of X-linked Dyskeratosis Congenita (DKCX) Cellular Defects Is not Directly Related to Dyskerin (DKC1) Activity in Ribosomal RNA Biogenesis or mRNA Translation

• Published in: Human mutation Vol. 34; no. 12; pp. 1698 - 1707
• Main Authors: Thumati, Naresh R., Zeng, Xi-Lei, Au, Hilda H. T., Jang, Christopher J., Jan, Eric, Wong, Judy M. Y.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2013; Hindawi Limited
• Subjects: Biosynthesis; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell-Free System; Chromosomes; DKC1; Dyskeratosis Congenita - genetics; Dyskeratosis Congenita - metabolism; dyskerin; Fibroblasts - metabolism; Gene Expression; Genetic Association Studies; Humans; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Biosynthesis; Protein synthesis; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; ribosomal RNA; Ribosome Subunits - metabolism; ribosomes; RNA, Ribosomal - chemistry; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; Severity of Illness Index; Stress, Physiological; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - metabolism; X-linked dyskeratosis congenita; ribosomes; ribosomal RNA; X-linked dyskeratosis congenita; DKC1; dyskerin
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22447

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‐DCT). 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 (WTT) and X‐DCT cells, with an internal ribosomal entry site translation assay, or by measuring total protein synthesis in live cells. X‐DCT cells and WTT 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. Telomere attrition is the single unifying disease etiology for DKCX and HHS patients. In addition to telomere synthesis defects, we propose that other genetic or environmental modifiers can accelerate telomere attrition. Together, the effect of these factors on telomere length influences the severity of individual DKCX cases. In turn, differential telomere attrition in affected tissues alters the presentation of clinical symptoms.