Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert

Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3597-602. doi: 10.1073/pnas.062549199.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromosome Aberrations
  • DNA-Binding Proteins
  • Gene Deletion
  • Genome
  • Heterozygote*
  • In Situ Hybridization, Fluorescence
  • Metaphase / genetics
  • Mice
  • Protein Transport
  • Stem Cells / cytology
  • Stem Cells / enzymology
  • Stem Cells / metabolism
  • Telomerase / genetics*
  • Telomerase / metabolism*
  • Telomere / enzymology*
  • Telomere / genetics
  • Telomere / metabolism*

Substances

  • DNA-Binding Proteins
  • Telomerase