title: Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects.
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.
authors.affiliation: Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Schmidt
authors.affiliation: Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Goldfarb
authors.affiliation: Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cech
authors.affiliation: Department of Chemistry &Biochemistry, University of Colorado, Boulder, Colorado, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Parker
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism*; D063326:Exosome Multienzyme Ribonuclease Complex / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000378:metabolism*; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D020871:RNA Stability; D019098:Telomerase / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; D009687:Nuclear Proteins; D012313:RNA; D012316:RNA Nucleotidyltransferases; D019098:Telomerase; C112148:DKC1 protein, human; C422952:telomerase RNA; C567954:TENT4B protein, human; C077044:EXOSC10 protein, human