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Molecular and Cellular Biology, October 2008, p. 6510-6520, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00777-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Disease-Associated Human Telomerase RNA Variants Show Loss of Function for Telomere Synthesis without Dominant-Negative Interference{triangledown}

Timothy M. Errington,{dagger} Dragony Fu,{ddagger} Judy M. Y. Wong,§ and Kathleen Collins*

Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720

Received 14 May 2008/ Returned for modification 11 July 2008/ Accepted 12 August 2008

Telomerase adds simple-sequence repeats to chromosome ends to offset the terminal sequence loss inherent in each cycle of genome replication. Inherited mutations in genes encoding subunits of the human telomerase holoenzyme give rise to disease phenotypes including hematopoietic failure and pulmonary fibrosis. Disease-associated variants of the human telomerase RNA are expressed in heterozygous combination with wild-type telomerase RNA. Here, we exploit a sensitized human primary cell assay system to investigate the biological function of disease-linked telomerase RNA variants and their impact on the function of coexpressed wild-type telomerase RNA. We find that telomerase RNA variants discovered in patients with dyskeratosis congenita or aplastic anemia show loss of function without any indication of dominant-negative impact on telomere maintenance by the coexpressed wild-type RNA. To reconcile this result with contradictory findings from reconstitution assays in vitro, we demonstrate that the lack of dominant-negative impact on telomere maintenance correlates with physiological assembly of active human telomerase holoenzyme ribonucleoproteins harboring monomers rather than higher-order multimers of telomerase RNA and telomerase reverse transcriptase. These findings support loss of function of telomerase RNA as a general mechanism of human disease.

* Corresponding author. Mailing address: Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200. Phone: (510) 643-1598. Fax: (510) 643-6791. E-mail: kcollins{at}berkeley.edu

{triangledown} Published ahead of print on 18 August 2008.

{dagger} Present address: Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, VA 22908.

{ddagger} Present address: Building 56-230, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02138.

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

Molecular and Cellular Biology, October 2008, p. 6510-6520, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00777-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Meznikova, M., Erdmann, N., Allsopp, R., Harrington, L. A. (2009). Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes. DMM 2: 620-626 [Abstract] [Full Text]  


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