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

Erkin Erdal,Adrian L Harris,Syed Haider,Peter J Mchugh,Jan Rehwinkel

doi:10.1101/gad.289769.116

Abstract

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.

Highlights

The host innate immune system is essential in the defense against potentially lethal infections by a broad range of pathogens (Takeuchi and Akira 2010)
IFN-related DNA damage resistance signature” (IRDS) expression measured by a clinical classifier comprised of seven IRDS genes (STAT1, MX1, ISG15, OAS1, IFIT1, IFIT3, and IFI44) identifies patients whose cancers are resistant to chemotherapy and radiotherapy
To further investigate whether DNA damage processing can lead to DNA fragments escaping the nucleus, a range of breast cancer cell lines (MCF7, BT474, MDA-MB-231, HCC1806, and T47D) was treated with ionizing radiation (IR) (X rays) or DNA-damaging chemotherapeutics that induce distinct forms of DNA damage

Summary

Introduction

The host innate immune system is essential in the defense against potentially lethal infections by a broad range of pathogens (Takeuchi and Akira 2010). Depending on the extent and nature of damage associated with the DSB termini, the nuclease activity of the Mre component of the Mre11–Rad50– NBS1 (MRX) complex is required to initiate resection, producing endonucleolytic incisions internally (5′) to the blocked end, providing a substrate for the 5′–3′ exonucleases that perform the long-range resection reactions (Symington and Gautier 2011; Cejka 2015). Two separate pathways have been identified that produce the 3′ overhang resection products of several thousand nucleotides that are required to promote HR in mitotic cells (Gravel et al 2008; Mimitou and Symington 2008; Zhu et al 2008; Cejka et al 2010; Niu et al 2010; Nimonkar et al 2011) One of these pathways is dependent on a 5′-to-3′ exonuclease 1 (EXO1) acting in concert with the DNA-unwinding activity provided by the Bloom (BLM) helicase. We present evidence that expression of DNA repair nucleases required to generate the cytosolic DNA fragments plays an important prognostic role in breast cancer, validating them as attractive therapeutic targets to overcome resistance to DNAdamaging therapies

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Conclusion