MRE11 mobilizes CGAS and drives ZBP1-dependent necroptosis

Recent data from Cho et al. demonstrate that the DNA repair protein MRE11 liberates CGAS from nucleosomes to license type I interferon secretion upon oncogenic stress and ionizing radiation.MRE11-mediated CGAS activation culminates in ZBP1-driven necroptosis, which is essential for limiting mammary oncogenesis.Mammalian cells are endowed with numerous systems that detect infectious threats, including (but not limited to) a variety of receptors that react to exogenous and/or ectopic nucleic acids by promoting cellular and organismal defense responses, which often involve the secretion of antimicrobial and pro-inflammatory cytokines like type I interferon (IFN). 1 While these systems have emerged as part of the pathogen-host co-evolution, abundant preclinical and clinical findings demonstrate that the recognition of immunogenic endogenous RNA and DNA species that are formed (or change subcellular localization) in response to stress is paramount for the preservation of organismal homeostasis, especially in the context of malignant transformation. 2A proficient response to aberrant or ectopic RNA and DNA species accumulating in cancer cells exposed to common cancer therapeutics (notably DNA-damaging agents such as radiotherapy) also appears to be critical for the elicitation of therapeuticallyrelevant anticancer immunity. 2Intriguingly, multiple proteins involved in the DNA damage response (DDR) including the exonuclease MRE11 homolog, double strand break repair nuclease (MRE11) are intimately connected to the sensing of endogenous nucleic acids. 3Specifically, cytosolic MRE11 promotes type I IFN secretion in response to DNA damage via a stimulator of interferon response cGAMP interactor 1 (STING1)-and interferon regulatory factor 3 (IRF3)-dependent mechanism. 4ecent data from Cho and colleagues extend our mechanistic understanding of this process by demonstrating that MRE11 promotes STING1 signaling by displacing the DNA sensor and STING1 activator cyclic GMP-AMP synthase (CGAS) from inhibitory interactions with chromatin.They also demonstrate that the ability of MRE11 to elicit proficient CGAS responses can culminate in the initiation of cell death via Z-DNA binding protein 1 (ZBP1)-driven necroptosis. 5ho et al. established an in vivo CRISPR screen harnessing a transgenic mouse model with conditional alleles for Mycn and cas9 expression and Trp53 deficiency (Rosa26 LSL-Mync/LSL-cas9 ;Trp53 fl/ fl