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Molecular and Cellular Biology, August 2004, p. 7024-7031, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7024-7031.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo

Y. Jeffrey Chiang,1* Michael T. Hemann,2 Karen S. Hathcock,1 Lino Tessarollo,3 Lionel Feigenbaum,4 William C. Hahn,5 and Richard J. Hodes1,6

Experimental Immunology Branch, National Cancer Institute,1 National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892,6 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,2 Mouse Cancer Genetics Program, Center for Cancer Research,3 Transgenic Mouse Model Laboratory, SAIC Frederick Inc., National Cancer Institute, Frederick, Maryland 21702,4 Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 021155

Received 16 February 2004/ Returned for modification 9 March 2004/ Accepted 12 May 2004

Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/– heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/– heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.

* Corresponding author. Mailing address: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Building 10, 4B36, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-1376. Fax: (301) 496-0887. E-mail: chiangj{at}mail.nih.gov.

Molecular and Cellular Biology, August 2004, p. 7024-7031, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7024-7031.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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