Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita
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.
- Copyright © 2006, Cold Spring Harbor Laboratory Press