Telomere maintenance by recombination in human cells

Dunham, Melissa A.; Neumann, Axel A.; Fasching, Clare L.; Reddel, Roger R.

doi:10.1038/82586

Cited by 768 publications

(660 citation statements)

References 28 publications

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“…The existence of an alternative telomerase-independent mechanism for telomere length preservation (ALT) in the lymphomas examined here cannot be ruled out completely. As no specific test for the ALT exists that can be applied to tissue samples, so far only indirect evidence can be obtained from the telomere length pattern (Bryan et al, 1995;Dunham et al, 2000). However, studies of telomere length pattern in B-NHL suggest that most of the lymphomas have telomeres that point to a telomerase-dependent pathway of telomere maintenance (Remes et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Klapper¹,

Krams²,

Qian

et al. 2003

Br J Cancer

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Telomere maintenance is a prerequisite for immortalisation, and in most malignant cells is carried out by telomerase, an enzyme that synthesises new telomeric repeats on the chromosome ends. In normal or reactive tissues with a high regenerative capacity, telomerase is regulated according to the telomere loss that occurs during proliferation. To evaluate the interaction of proliferation and telomerase activity in malignant lymphomas, we quantified telomerase expression in different non-Hodgkin lymphomas in comparison to normal or reactive lymph nodes. Surprisingly, the activity levels were the same in most of the lymphomas analysed as compared to reactive lymph nodes. Significantly higher activity was detected only in Burkitt's lymphoma. Telomerase activity correlated well with hTERT and c-myc expression, but was independent of proliferation. To evaluate interactions of telomere-binding protein expression on telomerase expression in non-Hodgkin lymphoma, the mRNA levels of TRF1, TRF2, tankyrase and hPif1 were assessed by real-time RT -PCR. We demonstrate here that the magnitude of telomerase upregulation does not necessarily reflect the requirement of telomere compensation caused by proliferation. Telomerase regulation in non-Hodgkin lymphomas is therefore uncoupled from proliferative stimuli found in reactive lymphoid tissue. We suggest that the upregulation of specific telomere-binding proteins like TRF2 may contribute to telomere maintenance in malignant lymphoma.

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Section: Discussionmentioning

confidence: 99%

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Klapper¹,

Krams²,

Qian

et al. 2003

Br J Cancer

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“…As malignant tumors develop, however, the resident cancer cells -in order to survive --must eventually acquire mechanisms to stabilize telomeres and prevent their erosion owing to cell division [14]. Thus, cancer cells frequently reactivate telomerase [15], or acquire an alternative mechanism for maintaining telomeres [16]. In addition, there is increasing evidence that dysfunctional telomeres may contribute to the development of aging phenotypes [7,8,11,13,17,18].…”

Section: Telomere Function Affects Cellular and Organismal Phenotypesmentioning

confidence: 99%

Cancer and aging: the importance of telomeres in genome maintenance

Rodier

Kim

Nijjar

et al. 2005

The International Journal of Biochemistry & Cell Biology

120

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Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure.

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“…A subset of tumors and about 50% of SV40-immortalized cell lines maintain their telomeres by one or more telomeraseindependent mechanisms referred to as alternative lengthening of telomeres (ALT) (Bryan et al, 1997). ALT pathways involve homologous recombination to replicate telomeric DNA (Dunham et al, 2000;Bailey et al, 2004). Analysis of post-replicative telomere exchanges using the chromosome orientation fluorescence in situ hybridization (CO-FISH) method showed a tight correlation between telomeric sister chromatid exchanges (T-SCEs) and ALT pathways (Bechter et al, 2004;Londono-Vallejo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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Most human tumor cells acquire immortality by activating the expression of telomerase, a ribonucleoprotein that maintains stable telomere lengths at chromosome ends throughout cell divisions. Other tumors use an alternative mechanism of telomere lengthening (ALT), characterized by high frequencies of telomeric sister chromatid exchanges (T-SCEs). Mechanisms of ALT activation are still poorly understood, but recent studies suggest that DNA hypomethylation of chromosome ends might contribute to the process by facilitating T-SCEs. Here, we show that ALT/T-SCE high tumor cells display low DNAmethylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCE high SV40-immortalized fibroblasts. Moreover, T-SCE rates were efficiently reduced by ectopic expression of active telomerase in ALT tumor cells, even though subtelomeric sequences remained hypomethylated. We also show that hypomethylation of subtelomeric sequences in ALT tumor cells is correlated with genome-wide hypomethylation of Alu repeats and pericentromeric Sat2 DNA sequences. Overall, this study suggests that, although subtelomeric DNA hypomethylation is often coincident with the ALT process in human tumor cells, it is not required for T-SCE.

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Telomere maintenance by recombination in human cells

Cited by 768 publications

References 28 publications

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation

Cancer and aging: the importance of telomeres in genome maintenance

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

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