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Alternative lengthening of telomeres in mammalian cells

Oncogene volume 21, pages 598–610 (2002)Cite this article

Abstract

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-specific binding proteins, and proteins involved in DNA recombination and replication. Activation of ALT during immortalization involves recessive mutations in genes that are as yet unidentified. 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 single-stranded 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 telomere-related parameters in cancer diagnosis and prognosis, and poses challenges for the design of anticancer therapeutics designed to inhibit telomere maintenance.

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Abbreviations

ALT:

alternative lengthening of telomeres

APB:

ALT-associated PML body

DSB:

double-strand break

ECTR:

extrachromosomal telomeric repeats

FISH:

fluorescent in situ hybridization

HPV:

human papillioma virus

HR:

homologous recombination

LFS:

Li-Fraumeni syndrome

PNB:

PML nuclear body

PD:

population doubling

SV40:

simion virus 40

TRD:

telomeric rapid deletion

TERT:

telomerase reverse transcriptase

TR:

telomerase RNA

TRF:

terminal restriction fragment.

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Acknowledgements

The authors thank Clare Fasching for comments on the manuscript. Work in the authors' laboratory is supported by Cancer Council NSW and the National Health and Medical Research Council of Australia.

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    Jeremy D Henson, Axel A Neumann, Thomas R Yeager & Roger R Reddel

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Henson, J., Neumann, A., Yeager, T. et al. Alternative lengthening of telomeres in mammalian cells. Oncogene 21, 598–610 (2002). https://doi.org/10.1038/sj.onc.1205058

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