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  • Original Paper
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hTERT associates with human telomeres and enhances genomic stability and DNA repair

Oncogene volume 22, pages 131–146 (2003)Cite this article

Abstract

Ectopic expression of telomerase in telomerase-silent cells is sufficient to overcome senescence and to extend cellular lifespan. We show here that the catalytic subunit of human telomerase (hTERT) crosslinks telomeres. This interaction is blocked by the telomere repeat binding factor 1, but not by a dominant negative form of this protein. It is also abolished by destruction of the RNA component of telomerase as well as by mutations in the hTERT protein. Ectopic expression of hTERT leads to transcriptional alterations of a subset of genes and changes in the interaction of the telomeres with the nuclear matrix. This is associated with reduction of spontaneous chromosome damage in G1 cells, enhancement of the kinetics of DNA repair and an increase in NTP levels. The effect on DNA repair is likely indirect as TERT does not directly affect DNA end rejoining in vitro or meiotic recombination in vivo. The observed effects of hTERT occurred rapidly before any significant lengthening of telomeres was observed. Our findings establish an intimate relationship between hTERT–telomere interactions and alteration in transcription of a subset of genes that may lead to increased genomic stability and enhanced repair of genetic damage. These novel functions of telomerase are distinct from its known effect on telomere length and have potentially important biological consequences.

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Acknowledgements

We thank Drs R Kucheralapati and Y Heyer for microarray facility, and Drs D Thanos and S Mitra for the suggestions on ChIP. We thank Dr Titia de Lange for providing us reagents for this study. Thanks are due to T. Rounsville for making adenovirus constructs. This work was supported by NIH Grant NS34746 and A-T Children's project to TKP, NCI CN-15015 to JWS and CA13696 to CSHY.

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Author notes

  1. George Iliakis

    Present address: University of Essen, D-45122, Essen, Germany

Authors and Affiliations

  1. Radiation and Cancer Biology Division, Washington University School of Medicine, St Louis, 63108, MO, USA

    Girdhar G Sharma, Arun Gupta, Sonu Dhar & Tej K Pandita

  2. College of Physicians and Surgeons, Columbia University, New York, 10032, NY, USA

    Girdhar G Sharma, Arun Gupta, Sonu Dhar, Charles S H Young & Tej K Pandita

  3. Thomas Jefferson University, Philadelphia, 19107, PA, USA

    Huichen Wang & George Iliakis

  4. Max-Plank-Institute for Molecular Genetics, Ihnestraße 73, Berlin, D-14195, Germany

    Harry Scherthan

  5. University of Texas, MDACC, Houston, 70330, TX, USA

    Varsha Gandhi

  6. University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Jerry W Shay

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Sharma, G., Gupta, A., Wang, H. et al. hTERT associates with human telomeres and enhances genomic stability and DNA repair. Oncogene 22, 131–146 (2003). https://doi.org/10.1038/sj.onc.1206063

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