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FEN1 contributes to telomere stability in ALT-positive tumor cells

Oncogene volume 28, pages 1162–1167 (2009)Cite this article

Abstract

Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase–bridge–breakage cycles, which further drive genome instability and thereby contribute to the transformation process.

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Acknowledgements

This work was supported by the Sidney Kimmel Foundation for Cancer Research and the Edward Mallinckrodt, Jr Foundation. AS was supported by the Lucille P Markey Program. SAS is a Sidney Kimmel Scholar. We are grateful to Yu Tao for help with statistical analyses and members of the Stewart Laboratory for valuable discussions.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA

    A Saharia & S A Stewart

  2. Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    S A Stewart

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  1. A Saharia
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  2. S A Stewart
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Correspondence to S A Stewart.

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Saharia, A., Stewart, S. FEN1 contributes to telomere stability in ALT-positive tumor cells. Oncogene 28, 1162–1167 (2009). https://doi.org/10.1038/onc.2008.458

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