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.

中文翻译：

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染色体外端粒重复DNA通过cGAS-STING DNA传感途径与ALT发生有关

染色体外端粒重复序列（ECTR）DNA是癌细胞的特质，癌细胞通过端粒的交替延长（ALT）途径维持端粒，但是ECTR在ALT发育中的作用仍然难以捉摸。我们发现在正常人成纤维细胞中诱导ECTRs激活了cGAS-STING-TBK1-IRF3信号转导轴，以触发IFNβ产生和I型干扰素反应，从而导致细胞增殖缺陷。相反，ALT癌细胞通常在感知细胞质DNA方面存在缺陷。我们发现STING表达在ALT癌细胞系和转化的ALT细胞中受到抑制。值得注意的是，还需要ALT抑制剂组蛋白H3.3和ATRX–Daxx组蛋白分子伴侣复合物来激活DNA传感途径。总的来说，