Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dyskeratosis Congenita / genetics*
  • Dyskeratosis Congenita / pathology
  • Exoribonucleases / genetics*
  • Germ-Line Mutation / genetics
  • HeLa Cells
  • Humans
  • Kinetics
  • RNA / genetics*
  • RNA Nucleotidyltransferases / genetics*
  • RNA Processing, Post-Transcriptional / genetics
  • Telomerase / genetics*


  • telomerase RNA
  • RNA
  • RNA Nucleotidyltransferases
  • TENT4B protein, human
  • Telomerase
  • Exoribonucleases
  • poly(A)-specific ribonuclease