Telomere Length Dynamics in Telomerase-Positive Immortal Human Cell Populations

Bryan, Tracy M.; Englezou, Anna; Dunham, Melissa A.; Reddel, Roger R.

doi:10.1006/excr.1997.3907

Cited by 98 publications

(81 citation statements)

References 46 publications

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“…This is consistent with a feedback mechanism of telomere length control which has been proposed in yeast (Shore, 1997). Also in support of such a proposal are studies that were conducted in our laboratory with telomerase positive 293 cells which revealed shortening high molecular weight TRF bands (Bryan et al, 1998). Another study of a human thyroid cancer cell line also showed occasional telomere shortening with no variation in levels of telomerase activity over continuing passages in culture (Jones et al, 1998).…”

Section: Discussionsupporting

confidence: 87%

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

et al. 1999

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Some immortalized cell lines maintain their telomeres in the absence of detectable telomerase activity by an alternative (ALT) mechanism. To study how telomere maintenance is controlled in ALT cells, we have fused an ALT cell line GM847 (SV40 immortalized human skin ®broblasts) with normal ®broblasts or with telomerase positive immortal human cell lines and have examined their proliferative potential and telomere dynamics. The telomeres in ALT cells are characteristically very heterogeneous in length, ranging from very short to very long. The ALT6normal hybrids underwent a rapid reduction in telomeric DNA and entered a senescencelike state. Immortal segregants rapidly reverted to the ALT telomere phenotype. Fusion of ALT cells to telomerase-positive immortal cells in the same immortalization complementation group resulted in hybrids that appeared immortal and also exhibited repression of the ALT telomere phenotype. In these hybrids, which were all telomerase-positive, we observed an initial rapid loss of most long telomeres, followed either by gradual loss of the remaining long telomeres at a rate similar to the rate of telomere shortening in normal telomerase-negative cells, or by maintenance of shortened telomeres. These data indicate the existence of a mechanism of rapid telomere deletion in human cells. They also demonstrate that normal cells and at least some telomerase-positive immortal cells contain repressors of the ALT telomere phenotype.

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Section: Discussionsupporting

confidence: 87%

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

et al. 1999

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“…While the length of telomeres decreases with each cell division in primary cells, the average telomere length of immortalized, telomerase-positive cells is generally stable during long-term culture (Counter et al, 1992;Counter et al, 1994;Klingelhutz et al, 1994;Bryan et al, 1998). Consistent with these observations, the mean TRF length in our AT5BIVA cell line did not obviously change within 12 mo of continuous cultivating and was very similar to the TRF lengths reported for the same cell line by other researchers (Xia et al, 1996;Smilenov et al, 1997).…”

Section: Tel1 Expression Leads To Telomere Lengthening In A-t Cellssupporting

confidence: 90%

The YeastTEL1Gene Partially Substitutes for HumanATMin Suppressing Hyperrecombination, Radiation-Induced Apoptosis and Telomere Shortening in A-T Cells

Fritz¹,

Friedl²,

Zwacka

et al. 2000

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Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

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“…In one study, however, expression of telomerase in a human ALT cell line resulted in reduced evidence of ALT activity in two of nine clones (Ford et al, 2001). One possible explanation might be that ALT may be switched o as a stochastic event in some cells (as has been demonstrated for telomerase in telomerase-positive cells (Bryan et al, 1998)) which do not therefore lose proliferative capacity when exogenous telomerase is present. Another explanation could be that ALT and telomerase may compete for common molecular components or access to the telomere, and that ALT can be repressed under circumstances where a particularly high level of a telomerase subunit such as TERT is present.…”

Section: Ability Of Alt and Telomerase Activity To Co-exist In Human mentioning

confidence: 98%

Alternative lengthening of telomeres in mammalian cells

et al. 2002

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Some immortalized mammalian cell lines and tumors maintain or increase the overall length of their telomeres in the absence of telomerase activity by one or more mechanisms referred to as alternative lengthening of telomeres (ALT). Characteristics of human ALT cells include great heterogeneity of telomere size (ranging from undetectable to abnormally long) within individual cells, and ALT-associated PML bodies (APBs) that contain extrachromosomal telomeric DNA, telomere-speci®c binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidenti®ed. Repressors of ALT activity are present in normal cells and some telomerase-positive cells. Telomere length dynamics in ALT cells suggest a recombinational mechanism. Inter-telomeric copying occurs, consistent with a mechanism in which singlestranded DNA at one telomere terminus invades another telomere and uses it as a copy template resulting in net increase in telomeric sequence. It is possible that t-loops, linear and/or circular extrachromosomal telomeric DNA, and the proteins found in APBs, may be involved in the mechanism. ALT and telomerase activity can co-exist within cultured cells, and within tumors. The existence of ALT adds some complexity to proposed uses of telomererelated parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.

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Telomere Length Dynamics in Telomerase-Positive Immortal Human Cell Populations

Cited by 98 publications

References 46 publications

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids

The YeastTEL1Gene Partially Substitutes for HumanATMin Suppressing Hyperrecombination, Radiation-Induced Apoptosis and Telomere Shortening in A-T Cells

Alternative lengthening of telomeres in mammalian cells

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