A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1

E Erdal, S Haider, J Rehwinkel, AL Harris… - Genes & …, 2017 - genesdev.cshlp.org
E Erdal, S Haider, J Rehwinkel, AL Harris, PJ McHugh
Genes & development, 2017genesdev.cshlp.org
Radiotherapy and chemotherapy are effective treatment methods for many types of cancer,
but resistance is common. Recent findings indicate that antiviral type I interferon (IFN)
signaling is induced by these treatments. However, the underlying mechanisms still need to
be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA
damage resistance signature (IRDS), which correlates strongly with resistance to
radiotherapy and chemotherapy across different tumors. Classically, during viral infection …
Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that antiviral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumors. 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 used during cancer therapy lead to the release of ssDNA fragments from the cell nucleus into the cytosol, engaging this innate immune response. We found that the factors that control DNA end resection during double-strand break repair, including the Bloom syndrome (BLM) helicase 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 tumors 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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