Article

Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway

  • Nature Structural & Molecular Biology 24, 11241131 (2017)
  • doi:10.1038/nsmb.3498
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Abstract

Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells. Notably, the ALT suppressors histone H3.3 and the ATRX–Daxx histone chaperone complex were also required to activate the DNA-sensing pathway. Collectively, our data suggest that the loss of the cGAS-STING pathway may be required to evade ECTR-induced anti-proliferation effects and permit ALT development, and this requirement may be exploited for treatments specific to cancers utilizing the ALT pathway.

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Acknowledgements

We thank R.R. Reddel (Children's Medical Research Institute) for providing cell line samples; M.-C. Yao, R.-H.Chen, M.-Z. Lai, C. Wen and J. Lingner for discussions; H.-C. S. Yen for the cGAS construct; T.E. Chen for technical help; and the Genomics Core, Bioinformatics-Biology Core and Imaging Core in the Institute of Molecular Biology at Academia Sinica for help with data collection and analysis. Research in the laboratory of L.-Y. Chen was supported by Career Development Award CDA-105-L01 from Academia Sinica and grants from the Ministry of Science and Technology (105-2311-B-001-055-MY3).

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Affiliations

  1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.

    • Yi-An Chen
    • , Yi-Ling Shen
    • , Hsuan-Yu Hsia
    • , Yee-Peng Tiang
    • , Tzu-Ling Sung
    •  & Liuh-Yow Chen
  2. Taiwan International Graduate Program in Molecular and Cellular Biology, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan.

    • Yi-An Chen
    •  & Liuh-Yow Chen

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Contributions

Y.-A.C. and L.-Y.C. designed the study. Y.-A.C. performed most of the experiments, with assistance from Y.-L.S., H.-Y.H. and Y.-P.T. Y.A.C., T.-L.S. and L.-Y.C. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Liuh-Yow Chen.

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