Deficiency in Translesion DNA polymerase ζ induces an innate immune response

DNA polymerase pol {zeta} is regarded as a specialized DNA polymerase for bypass of DNA lesions. In mammalian cells, pol {zeta} also contributes to genomic stability during normal DNA replication. Disruption of Rev3l (the catalytic subunit of pol {zeta}) 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 {zeta}-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 {zeta} and indicate that inhibition of pol {zeta} may be therapeutically useful by simultaneously increasing sensitivity to genotoxins and inducing a cytotoxic innate immune response.