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Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
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Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
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Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
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Journal Article
Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway
2017
Overview
The cGAS-STING cytoplasmic-DNA-sensing pathway is activated by accumulation of extrachromosomal telomere repeats, and this proliferation-inhibition mechanism is defective in ALT cancer cells.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/109
/ 13/89
/ 14/1
/ 14/32
/ 631/250
/ 96/21
/ Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ Cancer
/ Cell Proliferation - physiology
/ Cellular signal transduction
/ DNA
/ Humans
/ Interferon regulatory factor 3
/ Interferon Regulatory Factor-3 - metabolism
/ Interferon-beta - biosynthesis
/ Membrane Proteins - metabolism
/ Nuclear Proteins - metabolism
/ Nucleotidyltransferases - metabolism
/ Protein-Serine-Threonine Kinases - metabolism
/ RNA, Small Interfering - genetics
/ Signal Transduction - genetics
/ Telomere Homeostasis - genetics
/ Testing
/ X-linked Nuclear Protein - genetics
