Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects

Mutations in the human telomerase RNA (hTR), the telomerase RNP component dyskerin (DKC1), and the poly(A) ribonuclease (PARN) can lead to reduced levels of hTR and dyskeratosis congenita (DC). However, the enzymes and mechanisms responsible for hTR degradation are unknown. We demonstrate that defects in dyskerin binding lead to hTR degradation by PAPD5-mediated oligoadenylation promoting 3’ to 5’ degradation by EXOSC10, as well as decapping and 5’ to 3’ decay by the cytoplasmic DCP2 and XRN1 enzymes. PARN increases hTR levels by deadenylating hTR, thereby limiting its degradation by EXOSC10. Telomerase activity and proper hTR localization in dyskerin- or PARN-deficient cells can be rescued by knockdown of DCP2 and/or EXOSC10. Prevention of hTR RNA decay also leads to a rescue of localization of DC-associated hTR mutants. These results suggest that inhibition of RNA decay pathways might be a useful therapy for some telomere pathologies.