title: A Polyadenylation-Dependent 3' End Maturation Pathway Is Required for the Synthesis of the Human Telomerase RNA.
abstract: Telomere maintenance by the telomerase reverse transcriptase requires a noncoding RNA subunit that acts as a template for the synthesis of telomeric repeats. In humans, the telomerase RNA (hTR) is a non-polyadenylated transcript produced from an independent transcriptional unit. As yet, the mechanism and factors responsible for hTR 3' end processing have remained largely unknown. Here, we show that hTR is matured via a polyadenylation-dependent pathway that relies on the nuclear poly(A)-binding protein PABPN1 and the poly(A)-specific RNase PARN. Depletion of PABPN1 and PARN results in telomerase RNA deficiency and the accumulation of polyadenylated precursors. Accordingly, a deficiency in PABPN1 leads to impaired telomerase activity and telomere shortening. In contrast, we find that hTRAMP-dependent polyadenylation and exosome-mediated degradation function antagonistically to hTR maturation, thereby limiting telomerase RNA accumulation. Our findings unveil a critical requirement for RNA polyadenylation in telomerase RNA biogenesis, providing alternative approaches for telomerase inhibition in cancer.
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Duy
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Grenier St-Sauveur
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Bergeron
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dupuis-Sandoval
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Scott
authors.affiliation: RNA Group, Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada. Electronic address: f.bachand@usherbrooke.ca.
authors.forename: François
authors.initials: F
authors.lastname: Bachand
mesh_terms: D015153:Blotting, Western; D005095:Exoribonucleases / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D026723:Polyadenylation; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*
chemical_list: D005095:Exoribonucleases; D039122:Poly(A)-Binding Protein I; D012313:RNA; D019098:Telomerase; C576588:PABPN1 protein, human; C422952:telomerase RNA