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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 defec...

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Autores principales: Shukla, Siddharth, Schmidt, Jens C., Goldfarb, Katherine C., Cech, Thomas R., Parker, Roy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830462/
https://www.ncbi.nlm.nih.gov/pubmed/26950371
http://dx.doi.org/10.1038/nsmb.3184
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author Shukla, Siddharth
Schmidt, Jens C.
Goldfarb, Katherine C.
Cech, Thomas R.
Parker, Roy
author_facet Shukla, Siddharth
Schmidt, Jens C.
Goldfarb, Katherine C.
Cech, Thomas R.
Parker, Roy
author_sort Shukla, Siddharth
collection PubMed
description 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.
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spelling pubmed-48304622016-09-07 Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects Shukla, Siddharth Schmidt, Jens C. Goldfarb, Katherine C. Cech, Thomas R. Parker, Roy Nat Struct Mol Biol Article 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. 2016-03-07 2016-04 /pmc/articles/PMC4830462/ /pubmed/26950371 http://dx.doi.org/10.1038/nsmb.3184 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permissions information is available at www.nature.com/reprints. T.R.C. is on the board of directors of Merck, Inc.
spellingShingle Article
Shukla, Siddharth
Schmidt, Jens C.
Goldfarb, Katherine C.
Cech, Thomas R.
Parker, Roy
Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title_full Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title_fullStr Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title_full_unstemmed Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title_short Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects
title_sort inhibition of telomerase rna decay rescues telomerase deficiency caused by dyskerin or parn defects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830462/
https://www.ncbi.nlm.nih.gov/pubmed/26950371
http://dx.doi.org/10.1038/nsmb.3184
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