Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease

J Clin Invest. 2016 Sep 1;126(9):3377-82. doi: 10.1172/JCI87547. Epub 2016 Aug 2.


The telomerase RNA component (TERC) is a critical determinant of cellular self-renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease.

MeSH terms

  • DNA, Complementary / metabolism
  • Dyskeratosis Congenita / genetics
  • Exoribonucleases / genetics*
  • Fibroblasts / metabolism
  • Gene Deletion
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Lentivirus / genetics
  • Mutation
  • Phenotype
  • Protein Processing, Post-Translational*
  • RNA / genetics*
  • RNA Interference
  • RNA Nucleotidyltransferases / metabolism
  • RNA, Small Interfering / genetics
  • Skin / metabolism
  • Telomerase / genetics*
  • Telomerase / metabolism
  • Telomere / ultrastructure


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