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Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease

Journal of Clinical Investigation, ISSN: 1558-8238, Vol: 126, Issue: 9, Page: 3377-3382
2016
  • 45
    Citations
  • 0
    Usage
  • 45
    Captures
  • 1
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    45
  • Captures
    45
  • Mentions
    1
    • Blog Mentions
      1
      • Blog
        1

Article Description

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.

Bibliographic Details

Boyraz, Baris; Moon, Diane H; Segal, Matthew; Muosieyiri, Maud Z; Aykanat, Asli; Tai, Albert K; Cahan, Patrick; Agarwal, Suneet

American Society for Clinical Investigation

Medicine

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