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Molecular and Cellular Biology, March 1999, p. 2373-2379, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Analysis of Genomic Integrity and p53-Dependent G1 Checkpoint in Telomerase-Induced Extended-Life-Span Human Fibroblasts

Homayoun Vaziri,1,* Jeremy A. Squire,2 Tej K. Pandita,3 Grace Bradley,2 Robert M. Kuba,2 Haihua Zhang,2 Sandor Gulyas,2 Richard P. Hill,2 Garry P. Nolan,1 and Samuel Benchimol2

Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305-53321; Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G-2M9, Canada2; and Center for Radiological Research, Columbia University, New York, New York 100323

Received 2 November 1998/Accepted 9 December 1998

Life span determination in normal human cells may be regulated by nucleoprotein structures called telomeres, the physical ends of eukaryotic chromosomes. Telomeres have been shown to be essential for chromosome stability and function and to shorten with each cell division in normal human cells in culture and with age in vivo. Reversal of telomere shortening by the forced expression of telomerase in normal cells has been shown to elongate telomeres and extend the replicative life span (H. Vaziri and S. Benchimol, Curr. Biol. 8:279-282, 1998; A. G. Bodnar et al., Science 279:349-352, 1998). Extension of the life span as a consequence of the functional inactivation of p53 is frequently associated with loss of genomic stability. Analysis of telomerase-induced extended-life-span fibroblast (TIELF) cells by G banding and spectral karyotyping indicated that forced extension of the life span by telomerase led to the transient formation of aberrant structures, which were subsequently resolved in higher passages. However, the p53-dependent G1 checkpoint was intact as assessed by functional activation of p53 protein in response to ionizing radiation and subsequent p53-mediated induction of p21Waf1/Cip1/Sdi1. TIELF cells were not tumorigenic and had a normal DNA strand break rejoining activity and normal radiosensitivity in response to ionizing radiation.

* Corresponding author. Mailing address: Stanford University School of Medicine, Department of Molecular Pharmacology, Edward's Building, 300 Pasteur Dr., Stanford, CA 94305-5332. Phone: (650) 498-4398. Fax: (650) 725-2952. E-mail: vaziri{at}cmgm.stanford.edu.

Molecular and Cellular Biology, March 1999, p. 2373-2379, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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