Nuclear cGAS Blocks DNA Repair to Drive Tumorigenesis

Cyclic GMP–AMP synthase (cGAS) binds to pathogen-derived double-stranded cytosolic DNA to induce an innate immune response and type I IFN production. Recently, it has been shown that cGAS binds to damaged DNA present in genomic instability–derived micronuclei. To further elucidate the role of cGAS in DNA repair, Liu, Zhang, Wu, and colleagues treated human fibroblast cells with genotoxic agents in vitro to evaluate the response of cGAS to DNA damage. Genotoxic therapies resulted in the translocation of cGAS into intact nuclei, which was ablated upon the mutation of the tyrosine 215 (Y215) residue in cGAS. RNAi screening showed that the loss of B-lymphoid tyrosine kinase–mediated phosphorylation of Y215 resulted in the nuclear translocation of cGAS in response to DNA damage. Further, chromatin immunoprecipitation assays demonstrated that cGAS is recruited to site-specific double-stranded breaks (DSB) and interacts with γH2AX, a biomarker of DNA damage. Overexpression of cGAS inhibited homologous recombination repair (HRR) and suppressed the recruitment of the HRR factors RPA2 and RAD51 to DNA DSBs regardless of the presence or absence of type I IFN; conversely, ablation of cGAS enhanced HRR. Coimmunoprecipitation demonstrated the interaction of cGAS with poly(ADP-ribose) polymerase 1 (PARP1), which is involved in both HRR and base-excision repair, and overexpression of cGAS reduced the DNA damage–induced interaction between PARP1 and Timeless, which is crucial for HRR. Pharmacologic inhibition or enzymatically inactivating mutation of PARP1 abrogated the interaction of PARP1 with cGAS, and knockdown of PARP1 ablated cGAS-mediated inhibition of HRR. cGAS depletion reduced tumor cell proliferation and colony formation in vitro and tumor growth in vivo. Together, these findings elucidate a mechanism underlying the protumorigenic role of cGAS in HRR and suggest that therapeutically targeting the nuclear translocation of cGAS may enhance the efficacy of DNA damage–inducing cancer therapies.

Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 2018;563:131–6.

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