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Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

DNA polymerase pol ζ is regarded as a specialized DNA polymerase for bypass of DNA lesions. In mammalian cells, pol ζ also contributes to genomic stability during normal DNA replication. Disruption of Rev3l (the catalytic subunit of pol ζ) is toxic to cells and mice, with increased constitutive chromosome damage, including micronuclei. As the cellular manifestations of this genomic stress have remained unexplored, we measured genome-wide transcriptional changes by RNA-seq in pol ζ-defective cells. Expression of 1117 transcripts was altered by 4-fold or more in Rev3l knockout mouse embryonic fibroblasts (MEFs), with a pattern showing an induction of an innate immune response. We validated the increased expression of known interferon-stimulated genes (ISG) at the mRNA and protein levels. We found that the cGAS-STING axis, which senses cytosolic DNA, drives ISG expression in Rev3l knockout MEFs. These results reveal a new genome protective function of pol ζ and indicate that inhibition of pol ζ may be therapeutically useful by simultaneously increasing sensitivity to genotoxins and inducing a cytotoxic innate immune response.