Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert.
Prolonged growth of murine embryonic stem (ES) cells lacking the telomerase reverse transcriptase, mTert, results in a loss of telomere DNA and an increased incidence of end-to-end fusions and aneuploidy. Furthermore, loss of only one copy of mTert also results in telomere shortening intermediate between wild-type (wt) and mTert-null ES cells [Liu, Y., Snow, B. E., Hande, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, A., Siderovski, D. P., Lansdorp, P. M., Robinson, M. O. & Harrington, L. (2000) Curr. Biol. 10, 1459-1462]. Unexpectedly, although average telomere length in mTert(+/-) ES cells declined to a similar level as mTert-null ES cells, mTert(+/-) ES cell lines retained a minimal telomeric DNA signal at all chromosome ends. Consequently, no end-to-end fusions and genome instability were observed in the latest passages of mTert(+/-) ES cell lines. These data uncover a functional distinction between the dosage-dependent function of telomerase in average telomere-length maintenance and the selective maintenance of critically short telomeres in cells heterozygous for mTert. In normal and tumor cells, we suggest that telomerase activity insufficient to maintain a given average telomere length may, nonetheless, provide a protective advantage from end-to-end fusion and genome instability.
Liu
Yie
Y
Ontario Cancer Institute/Amgen Research Institute, Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, ON, Canada.
Kha
Hue
H
Ungrin
Mark
M
Robinson
Murray O
MO
Harrington
Lea
L
D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D016678:Genome; D006579:Heterozygote; D017404:In Situ Hybridization, Fluorescence; D008677:Metaphase / Q000235:genetics; D051379:Mice; D021381:Protein Transport; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D019098:Telomerase