| Summary: | Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that anti-viral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of interferon-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumours. Classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells can initiate type I IFN signaling. Here, we demonstrate that DNA damaging modalities employed during cancer therapy lead to the release of single-stranded DNA fragments from the cell nucleus into the cytosol, engaging this innate immune response. We have found that the factors that control DNA end-resection during double-strand break repair, including the Bloom syndrome helicase (BLM) and Exonuclease 1 (EXO1) play a major role in generating these DNA fragments and that the cytoplasmic 3’-5’ exonuclease Trex1 is required for their degradation. Analysis of mRNA expression profiles in breast tumours demonstrates that those with lower Trex1 and higher BLM and EXO1 expression levels are associated with poor prognosis. Targeting BLM and EXO1 could therefore represent a novel approach for circumventing the IRDS produced in response to cancer therapeutics.
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