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

Oncogene volume 28, pages 1682–1693 (2009)Cite this article

Abstract

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-SCEhigh tumor cells display low DNA-methylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCEhigh 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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Acknowledgements

We are grateful to M Swinarska, F Brasseur, W Wright, F Fuks, J Lingner, F d'Adda di Fagagna, F Journe, H Id Boufker and C Heirman for the generous gifts of cell lines and plasmids. We thank all the members of the GENEPI group for their constant support and help. This study was supported by the Fonds National de la Recherche Scientifique (FNRS), Belgium. GT is supported by a PhD fellowship grant from Télévie/FNRS. AL is supported by a post-doctoral grant from the FNRS. Work in the ‘Telomere&Cancer’ laboratory is supported by grants from ANR, ARC, INCa and La Ligue.

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Authors and Affiliations

  1. Faculty of Medicine, Genetic and Epigenetic Alterations of The Genome Group, de Duve Institute, Catholic University of Louvain, Brussels, Belgium

    G Tilman, A Loriot, A Van Beneden, C De Smet & A Decottignies

  2. Telomeres and Cancer Laboratory, Institut Curie, Rue d'Ulm, Paris Cedex, France

    N Arnoult & J A Londoño-Vallejo

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  1. G Tilman
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  2. A Loriot
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  7. A Decottignies
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Correspondence to A Decottignies.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Tilman, G., Loriot, A., Van Beneden, A. et al. Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells. Oncogene 28, 1682–1693 (2009). https://doi.org/10.1038/onc.2009.23

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