1. ¹Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
2. ²Department of Biochemistry, Brain Korea 21 Program, Yonsei University, Seoul, Republic of Korea
3. ³Department of Anatomy, College of Medicine, Brain Korea 21 Program, Korea University, Seoul, Republic of Korea
4. ⁴Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
5. ⁵Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
6. ⁶Department of Medicine, Harvard Medical School, Boston, MA, USA
7. ⁷Department of Gene Mechanisms, Kyoto University, Kyoto, Japan

Correspondence: Professor H-W Lee, Department of Biochemistry, Yonsei University, 134 Sinchon-dong, Seoul 120-749, Republic of Korea. E-mail: hwl@yonsei.ac.kr

⁸These authors contributed equally to this work.

⁹Current address: Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Received 10 October 2007; Revised 27 November 2007; Accepted 11 December 2007; Published online 28 January 2008.

Abstract

The expression level of the telomerase catalytic subunit (telomerase reverse transcriptase, TERT) positively correlates with cell survival after exposure to several lethal stresses. However, whether the protective role of TERT is independent of telomerase activity has not yet been clearly explored. Here, we genetically evaluated the protective roles of both TERT and telomerase activity against cell death induced by staurosporine (STS) and N-methyl-D-aspartic acid (NMDA). First generation (G1) TERT-deficient mouse embryonic fibroblasts (MEFs) displayed an increased sensitivity to STS, while TERT transgenic MEFs were more resistant to STS-induced apoptosis than wild-type. Deletion of the telomerase RNA component (TERC) failed to alter the sensitivity of TERT transgenic MEFs to STS treatment. Similarly, NMDA-induced excitotoxic cell death of primary neurons was suppressed by TERT, but not by TERC both in vitro and in vivo. Specifically, NMDA accelerated death of TERT-deficient mice, while TERT transgenic mice showed enhanced survival when compared with wild-type littermates after administration of NMDA. In addition, the transgenic expression of TERT protected motor neurons from apoptosis induced by sciatic nerve axotomy. These results indicate that telomerase activity is not essential for the protective function of TERT. This telomerase activity-independent TERT function may contribute to cancer development and aging independently of telomere lengthening.