Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs.
Functional RNAs are processed according to cues from precursor expression context. The presence of an H/ACA motif within the human telomerase RNA (hTR) suggested that telomerase might utilize the biogenesis pathway of an H/ACA small nucleolar RNA. Here, we have investigated the requirements for processing, stability, and function of hTR. Instead of a biogenesis pathway dependent on transcription context or precursor sequence, we find that maturation of hTR requires cooperation of the H/ACA motif and an additional motif unique to the hTR H/ACA domain. This telomerase-specific hTR element is mutated in dyskeratosis congenita, and the disease-associated hTR substitution impairs RNA accumulation. Disease-associated hTR variants with sequence changes outside the H/ACA domain do not affect RNA processing or stability; they instead impose a catalytic defect. Our results reveal differences between the biogenesis of hTR and other H/ACA-motif RNAs and demonstrate distinct mechanisms of telomerase inhibition in human disease.
Fu
Dragony
D
Department of Molecular and Cell Biology, 401 Barker Hall, University of California at Berkeley, 97420, USA.
Collins
Kathleen
K
D020134:Catalytic Domain / Q000235:genetics; D002466:Cell Nucleolus / Q000201:enzymology / Q000235:genetics*; D002478:Cells, Cultured; D019871:Dyskeratosis Congenita / Q000201:enzymology / Q000235:genetics; D005057:Eukaryotic Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics; D020537:RNA, Small Nucleolar / Q000096:biosynthesis* / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D020537:RNA, Small Nucleolar; D012313:RNA; D012319:RNA Polymerase II; D019098:Telomerase