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Telomere length dynamics and chromosomal instability in cells derived from telomerase mice.

Hande MP, Samper E, Lansdorp P, Blasco MA - J. Cell Biol. (1999)

Bottom Line: Interestingly, the most frequent fusions found in mTER-/- cells were homologous fusions involving chromosome 2.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.

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.

ABSTRACT
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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Model of telomere dynamics and chromosomal instability during tumor progression. Telomere shortening could occur during the initial stages of tumor progression if cells divide in  the absence of compensating telomere lengthening mechanisms.  Telomere shortening to a critical length eventually triggers chromosomal instability as described in this paper. At this point, telomere maintenance mechanisms can be activated and selected to  allow immortal growth. The preferred mechanism to maintain  telomeres in tumor cells is the activation of the enzyme telomerase (reviewed in Shay and Bacchetti, 1996). However, the results shown in this paper indicate that in the absence of telomerase activity alternative telomere-maintaining mechanisms are  activated as a consequence telomere shortening.
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Figure 6: Model of telomere dynamics and chromosomal instability during tumor progression. Telomere shortening could occur during the initial stages of tumor progression if cells divide in the absence of compensating telomere lengthening mechanisms. Telomere shortening to a critical length eventually triggers chromosomal instability as described in this paper. At this point, telomere maintenance mechanisms can be activated and selected to allow immortal growth. The preferred mechanism to maintain telomeres in tumor cells is the activation of the enzyme telomerase (reviewed in Shay and Bacchetti, 1996). However, the results shown in this paper indicate that in the absence of telomerase activity alternative telomere-maintaining mechanisms are activated as a consequence telomere shortening.

Mentions: In general, the types of chromosomal aberrations detected in mTER−/− cell lines are similar to the ones described in tumor cells, supporting the notion that telomere loss is one of the main inducers of chromosomal instability in tumors (reviewed in de Lange, 1995). In agreement with this, tumors generally have short telomeres (reviewed in de Lange, 1995) probably because telomere loss is not compensated at the earlier steps of tumorigenesis. Telomere shortening would lead to chromosomal instability associated with end-to-end fusions and translocations of the types described in this work, favoring the allelic loss of tumor suppressor genes, such as p53 in the case of mouse chromosome 11 or human chromosome 17 (Martens et al., 1998). Our data agrees with the idea that when telomeres are critically short and there is a high degree of chromosomal instability telomere-maintenance mechanisms are activated and selected (see Fig. 6 for model). These mechanisms, which can be either telomerase dependent (reviewed in Shay and Bacchetti, 1997) or independent (this paper and Bryan et al., 1995, 1997), can prevent telomeres from further shortening, allowing the immortal growth of cells that have critically short telomeres and a high degree of genetic instability. In this regard, mTER−/− mice from late generations show an increased cancer incidence than the wt counterparts (Rudolph et al., 1999).


Telomere length dynamics and chromosomal instability in cells derived from telomerase mice.

Hande MP, Samper E, Lansdorp P, Blasco MA - J. Cell Biol. (1999)

Model of telomere dynamics and chromosomal instability during tumor progression. Telomere shortening could occur during the initial stages of tumor progression if cells divide in  the absence of compensating telomere lengthening mechanisms.  Telomere shortening to a critical length eventually triggers chromosomal instability as described in this paper. At this point, telomere maintenance mechanisms can be activated and selected to  allow immortal growth. The preferred mechanism to maintain  telomeres in tumor cells is the activation of the enzyme telomerase (reviewed in Shay and Bacchetti, 1996). However, the results shown in this paper indicate that in the absence of telomerase activity alternative telomere-maintaining mechanisms are  activated as a consequence telomere shortening.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132934&req=5

Figure 6: Model of telomere dynamics and chromosomal instability during tumor progression. Telomere shortening could occur during the initial stages of tumor progression if cells divide in the absence of compensating telomere lengthening mechanisms. Telomere shortening to a critical length eventually triggers chromosomal instability as described in this paper. At this point, telomere maintenance mechanisms can be activated and selected to allow immortal growth. The preferred mechanism to maintain telomeres in tumor cells is the activation of the enzyme telomerase (reviewed in Shay and Bacchetti, 1996). However, the results shown in this paper indicate that in the absence of telomerase activity alternative telomere-maintaining mechanisms are activated as a consequence telomere shortening.
Mentions: In general, the types of chromosomal aberrations detected in mTER−/− cell lines are similar to the ones described in tumor cells, supporting the notion that telomere loss is one of the main inducers of chromosomal instability in tumors (reviewed in de Lange, 1995). In agreement with this, tumors generally have short telomeres (reviewed in de Lange, 1995) probably because telomere loss is not compensated at the earlier steps of tumorigenesis. Telomere shortening would lead to chromosomal instability associated with end-to-end fusions and translocations of the types described in this work, favoring the allelic loss of tumor suppressor genes, such as p53 in the case of mouse chromosome 11 or human chromosome 17 (Martens et al., 1998). Our data agrees with the idea that when telomeres are critically short and there is a high degree of chromosomal instability telomere-maintenance mechanisms are activated and selected (see Fig. 6 for model). These mechanisms, which can be either telomerase dependent (reviewed in Shay and Bacchetti, 1997) or independent (this paper and Bryan et al., 1995, 1997), can prevent telomeres from further shortening, allowing the immortal growth of cells that have critically short telomeres and a high degree of genetic instability. In this regard, mTER−/− mice from late generations show an increased cancer incidence than the wt counterparts (Rudolph et al., 1999).

Bottom Line: Interestingly, the most frequent fusions found in mTER-/- cells were homologous fusions involving chromosome 2.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.

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus