Format

Send to

Choose Destination
Nat Struct Mol Biol. 2016 Apr;23(4):286-92. doi: 10.1038/nsmb.3184. Epub 2016 Mar 7.

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

Author information

1
Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.
2
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Abstract

Mutations in the human telomerase RNA component (hTR), the telomerase ribonucleoprotein component dyskerin (DKC1) and the poly(A) RNase (PARN) can lead to reduced levels of hTR and to 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, which promotes 3'-to-5' degradation by EXOSC10, as well as decapping and 5'-to-3' decay by the cytoplasmic DCP2 and XRN1 enzymes. PARN increased hTR levels by deadenylating hTR, thereby limiting its degradation by EXOSC10. Telomerase activity and proper hTR localization in dyskerin- or PARN-deficient cells were rescued by knockdown of DCP2 and/or EXOSC10. Prevention of hTR RNA decay also led 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.

PMID:
26950371
PMCID:
PMC4830462
DOI:
10.1038/nsmb.3184
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center