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

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 doublestrand 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.

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

“…Furthermore, expression of GFP‐hcGAS in HEK293T cells that lack endogenous cGAS and STING (Sun et al , ) impaired DSB repair in these cells (Fig EV3B), but, as expected, failed to restore the IFNB1 response (Fig EV3C). Thus, while essential for the induction of inflammatory genes following DNA damage via STING (Hartlova et al , ; Erdal et al , ), cGAS also promotes DNA damage by inhibiting DSB repair independently of STING.…”

Mitotic progression following DNA damage enables pattern recognition within micronuclei

“…These findings firmly establish a significant relationship between the presence of micronuclei and inflammatory signaling. We cannot ascribe the inflammatory response solely to micronuclei as small DNA fragments in the cytoplasm could also contribute to cGAS-STING activation 10, 21 . However, our data show robust relocalization of cGAS to the micronucleus and activation of inflammatory responses within these micronucleated cells.…”

Length does matter for cGAS

“…Given the length of viral and bacterial DNA genomes/products, which is generally greater than hundreds of kilobases, such sensitivity of cGAS to long dsDNA should allow for the rapid detection of infection, before its amplification. As such, assuming that endogenous DNA products are limited to shorter sizes (presumably less than 100 nt) [5,7], it is the length of pathogenic DNAs that ensures their selective detection by cGAS over that of self-DNAs. Further studies investigating the activation of cGAS during viral and bacterial infections should help confirm this high sensitivity of cGAS for longer DNAs at early stages of infection, together with its relevance to other types of DNA products including ssDNAs and DNA: RNA hybrids.…”