Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita

  1. Judy M.Y. Wong1 and
  2. Kathleen Collins2
  1. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA

Abstract

Dyskeratosis congenita (DC) patients suffer a progressive and ultimately fatal loss of hematopoietic renewal correlating with critically short telomeres. The predominant X-linked form of DC results from substitutions in dyskerin, a protein required both for ribosomal RNA (rRNA) pseudouridine modification and for cellular accumulation of telomerase RNA (TER). Accordingly, alternative models have posited that the exhaustion of cellular renewal in X-linked DC arises as a primary consequence of ribosome deficiency or telomerase deficiency. Here we test, for the first time, whether X-linked DC patient cells are compromised for telomerase function at telomeres. We show that telomerase activation in family-matched control cells allows telomere elongation and telomere length maintenance, while telomerase activation in X-linked DC patient cells fails to prevent telomere erosion with proliferation. Furthermore, we demonstrate by phenotypic rescue that telomere defects in X-linked DC patient cells arise solely from reduced accumulation of TER. We also show that X-linked DC patient cells averted from premature senescence support normal levels of rRNA pseudouridine modification and normal kinetics of rRNA precursor processing, in contrast with phenotypes reported for a proposed mouse model of the human disease. These findings support the significance of telomerase deficiency in the pathology of X-linked DC.

Keywords

Footnotes

  • 1 Present address: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver B.C., Canada V6T 1Z3.

  • 2 Corresponding author.

    2 E-MAIL kcollins{at}berkeley.edu; FAX (510) 643-6334.

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1476206.

    • Received July 31, 2006.
    • Accepted August 28, 2006.
| Table of Contents

G&D Most Read

View all ...

Life Science Alliance