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Mol Cell. 2019 May 16;74(4):688-700.e3. doi: 10.1016/j.molcel.2019.02.033. Epub 2019 Mar 28.

Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease.

Author information

1
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford, CA 94305, USA.
3
Dipartimento di Biologia e Biotecnologie, Sapienza University of Rome, Rome, Italy.
4
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: sartandi@stanford.edu.

Abstract

Mutations in RNA-processing enzymes are increasingly linked to human disease. Telomerase RNA and related noncoding RNAs require 3' end-processing steps, including oligoadenylation. Germline mutations in poly(A)ribonuclease (PARN) cause accumulation of extended human telomerase RNA (hTR) species and precipitate dyskeratosis congenita and pulmonary fibrosis. Here, we develop nascent RNAend-seq to measure processing rates of RNA precursors. We find that mature hTR derives from extended precursors but that in PARN-mutant cells hTR maturation kinetically stalls and unprocessed precursors are degraded. Loss of poly(A)polymerase PAPD5 in PARN-mutant cells accelerates hTR maturation and restores hTR processing, indicating that oligoadenylation and deadenylation set rates of hTR maturation. The H/ACA domain mediates hTR maturation by precisely defining the 3' end, recruiting poly(A)polymerase activity, and conferring sensitivity to PARN regulation. These data reveal a feedforward circuit in which post-transcriptional oligoadenylation controls RNA maturation kinetics. Similar alterations in RNA processing rates may contribute to mechanisms of RNA-based human disease.

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PMID:
30930056
PMCID:
PMC6525023
[Available on 2020-05-16]
DOI:
10.1016/j.molcel.2019.02.033
[Indexed for MEDLINE]

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