Block in Anaphase Chromosome Separation Caused by a Telomerase Template Mutation

Kirk, Karen E.; Harmon, Brian; Reichardt, Isabel K.; Sedat, John W.; Blackburn, Elizabeth H.

doi:10.1126/science.275.5305.1478

Cited by 195 publications

(139 citation statements)

References 20 publications

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“…These changes are indicative of cell death by mitotic catastrophe. Previous studies in human ALT cells and in lower eucaryotes have shown that mutated telomeres have deleterious effects on cell viability and result in cell cycle abnormalities and cell death by mitotic catastrophe (Yu et al, 1990;Kirk et al, 1997;Smith and Blackburn, 1999;Guiducci et al, 2001;Lin et al, 2004). Thus, although the expression of MuA-hTR does not affect cell viability in normal growth conditions, it may enhance the antiproliferative effects of doxorubicin, resulting in higher drug sensitivity compared to control cells.…”

Section: Discussionmentioning

confidence: 96%

Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance

2006

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Telomerase is a ribonucleoprotein complex that maintains the stability of chromosome ends and regulates replicative potential. Telomerase is upregulated in over 85% of human tumors, but not in adjacent normal tissues and represents a promising target for anticancer therapy. Most telomerase-based therapies rely on the inhibition of telomerase activity and require extensive telomere shortening before inducing any antiproliferative effect. Disturbances of telomere structure rather than length may be more effective in inducing cell death. Telomerase RNA subunits (hTRs) with mutations in the template region reconstitute active holoenzymes that incorporate mutated telomeric sequences. Here, we analysed the feasibility of an anticancer approach based on the combination of telomere destabilization and conventional chemotherapeutic drugs. We show that a mutant template hTR dictates the synthesis of mutated telomeric repeats in telomerase-positive cancer cells, without significantly affecting their viability and proliferative ability. Nevertheless, the mutant hTR increased sensitivity to anticancer drugs in cells with different initial telomere lengths and mechanisms of telomere maintenance and without requiring overall telomere shortening. This report is the first to show that interfering with telomere structure maintenance in a telomerase-dependent manner may be used to increase the susceptibility of tumor cells to anticancer drugs and may lead to the development of a general therapy for the treatment of human cancers.

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Section: Discussionmentioning

confidence: 96%

Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance

2006

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“…More interestingly, cell lines derived from AT patients have shortened telomere lengths (Metcalfe et al, 1996;Pandita et al, 1995;Xia et al, 1996) and defected G2/M checkpoint (Beamish et al, 1994;Rudolph and Latt, 1989). Finally, mutations in the Tetrahymena telomeric DNA sequence has been shown to cause a block in anaphase chromosome separation (Kirk et al, 1997). Collectively, these results suggest that telomeres may be important for regulation of mitosis.…”

Section: Introductionmentioning

confidence: 64%

Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors

et al. 2001

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Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 a ects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells ®rst accumulated in mitosis and strongly stained with the mitosis-speci®c MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was signi®cantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can speci®cally induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Signi®cantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were signi®cantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential. Oncogene (2001) 20, 1497 ± 1508.

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“…Recently, telomeric associations have been reported as a consequence of mutations in the UbcD1 gene in Drosophila melanogaster (Cenci et al, 1997), as well as mutations in a telomerase template in Tetrahymena thermophila (Kirk et al, 1997). To determine whether ATM function in¯uences TA, we examined metaphase spreads and found that RKO cells expressing dominant-negative fragments exhibited a 3 ± 6-fold higher frequency of cells with TA compared to parental and control RKO cells (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Influence of ATM function on telomere metabolism

Smilenov

Morgan²,

Mellado

et al. 1997

Oncogene

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The ATM gene product, which is defective in the cancerprone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL1 gene of yeast, mutations of which lead to shortened telomeres. To test the hypothesis that the ATM gene product is involved in telomere metabolism, we examined telomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to transfected controls had a higher frequency of cells with TA and shortened telomeres, but no detectable change in telomerase activity. In addition, the percentage of cells with TA after gamma irradiation was higher in the transfected RKO cells with dominant negative activity of the ATM gene, compared to control cells. SV40 transformed ®broblasts derived from an A-T patient and transfected with a complementing carboxyl terminal kinase region of the ATM gene had a reduced frequency of cells with TA, with no eect on the telomere length or telomerase activity. The present studies using isogenic cells with manipulated ATM function demonstrate a role for the ATM gene product in telomere metabolism.

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Block in Anaphase Chromosome Separation Caused by a Telomerase Template Mutation

Cited by 195 publications

References 20 publications

Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance

Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance

Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors

Influence of ATM function on telomere metabolism

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