To study the effect of continued telomere shortening on chromosome stability, we have analyzed the telomere length of two individual chromosomes (chromosomes 2 and 11) in fibroblasts derived from wild-type mice and from mice lacking the mouse telomerase RNA (mTER) gene using quantitative fluorescence in situ hybridization. Telomere length at both chromosomes decreased with increasing generations of mTER−/− mice. At the 6th mouse generation, this telomere shortening resulted in significantly shorter chromosome 2 telomeres than the average telomere length of all chromosomes. Interestingly, the most frequent fusions found in mTER−/− cells were homologous fusions involving chromosome 2. Immortal cultures derived from the primary mTER−/− cells showed a dramatic accumulation of fusions and translocations, revealing that continued growth in the absence of telomerase is a potent inducer of chromosomal instability. Chromosomes 2 and 11 were frequently involved in these abnormalities suggesting that, in the absence of telomerase, chromosomal instability is determined in part by chromosome-specific telomere length. At various points during the growth of the immortal mTER−/− cells, telomere length was stabilized in a chromosome-specific man-ner. This telomere-maintenance in the absence of telomerase could provide the basis for the ability of mTER−/− cells to grow indefinitely and form tumors.
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22 February 1999
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February 22 1999
Telomere Length Dynamics and Chromosomal Instability in Cells Derived from Telomerase Null Mice
M. Prakash Hande,
M. Prakash Hande
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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Enrique Samper,
Enrique Samper
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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Peter Lansdorp,
Peter Lansdorp
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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María A. Blasco
María A. Blasco
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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M. Prakash Hande
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Enrique Samper
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Peter Lansdorp
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
María A. Blasco
*Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain; ‡Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada; and §Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Address correspondence to María A. Blasco, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Cantoblanco, Madrid E-28049, Spain. Tel.: 34 91 585 4846. Fax: 34 91 372 0493. E-mail: [email protected]
Received:
June 29 1998
Revision Received:
January 15 1999
Online ISSN: 1540-8140
Print ISSN: 0021-9525
1999
J Cell Biol (1999) 144 (4): 589–601.
Article history
Received:
June 29 1998
Revision Received:
January 15 1999
Citation
M. Prakash Hande, Enrique Samper, Peter Lansdorp, María A. Blasco; Telomere Length Dynamics and Chromosomal Instability in Cells Derived from Telomerase Null Mice . J Cell Biol 22 February 1999; 144 (4): 589–601. doi: https://doi.org/10.1083/jcb.144.4.589
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