title: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
authors.forename: Judy M Y
authors.initials: JM
authors.lastname: Wong
authors.forename: Kathleen
authors.initials: K
authors.lastname: Collins
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D041321:Chromosomes, Human, X / Q000648:ultrastructure*; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D012313:RNA; D012335:RNA, Ribosomal / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D019098:Telomerase / Q000737:chemistry* / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase