The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita

Xi Lei Zeng, Naresh R. Thumati, Helen B. Fleisig, Kyle R. Hukezalie, Sharon A. Savage, Neelam Giri, Blanche P. Alter, Judy M Y Wong

Research output: Contribution to journalArticlepeer-review

Abstract

X-linked dyskeratosis congenita (X-DC) is caused by mutations in the housekeeping nucleolar protein dyskerin. Amino acid changes associated with X-DC are remarkably heterogeneous. Peripheral mononuclear blood cells and fibroblasts isolated from X-DC patients harbor lower steady-state telomerase RNA (TER) levels and shorter telomeres than healthy age-matched controls. Previously, we showed that retroviral expression of recombinant TER, together with expression of recombinant telomerase reverse transcriptase, restored telomere maintenance and proliferative capacity in X-DC patient cells. Using rare X-DC isoforms (ΔL37 and A386T dyskerin), we showed that telomere maintenance defects observed in X-DC are solely due to decreased steady-state levels of TER. Disease-associated reductions in steady-state TER levels cause deficiencies in telomere maintenance. Here, we confirm these findings in other primary X-DC patient cell lines coding for the most common (A353V dyskerin) and more clinically severe (K314R and A353V dyskerin) X-DC isoforms. Using cell lines derived from these patients, we also examined the steady-state levels of other hinge-ACA motif RNAs and did not find differences in their in vivo accumulations. We show, for the first time, that purified telomerase holoenzyme complexes from different X-DC cells have normal catalytic activity. Our data confirm that dyskerin promotes TER stability in vivo, endorsing the development of TER supplementation strategies for the treatment of X-DC.

Original languageEnglish (US)
Article numberddr504
Pages (from-to)721-729
Number of pages9
JournalHuman Molecular Genetics
Volume21
Issue number4
DOIs
StatePublished - Feb 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Fingerprint Dive into the research topics of 'The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita'. Together they form a unique fingerprint.

Cite this