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

Nat Struct Mol Biol. 2017 Dec;24(12):1124-1131. doi: 10.1038/nsmb.3498. Epub 2017 Nov 6.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • DNA / genetics
  • Humans
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon-beta / biosynthesis*
  • Membrane Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleotidyltransferases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction / genetics
  • Telomere / genetics*
  • Telomere Homeostasis / genetics
  • X-linked Nuclear Protein / genetics
  • X-linked Nuclear Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DAXX protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • STING protein, human
  • Interferon-beta
  • DNA
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • ATRX protein, human
  • X-linked Nuclear Protein