Disruption of DNA polymerase ζ engages an innate immune response

Inmammalian cells, specialized DNA polymerase zeta (pol zeta) contributes to genomic stability during normal DNA replication. Disruption of the catalytic subunit Rev3l is toxic and results in constitutive chromosome damage, including micronuclei. As manifestations of this genomic stress are unknown, we examined the transcriptome of pol zeta-defective cells by RNA sequencing (RNA-seq). Expression of 1,117 transcripts is altered by >= 4-fold in Rev3l-disrupted cells, with a pattern consistent with an induction of an innate immune response. Increased expression of interferon-stimulated genes at the mRNA and protein levels in pol zeta-defective cells is driven by the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-signaling partner stimulator of interferon genes (STING) pathway. Expression of key interferon-stimulated chemokines is elevated in basal epithelial mouse skin cells with a disruption of Rev3l. These results indicate that the disruption of pol zeta may simultaneously increase sensitivity to genotoxins and potentially engage parts of the innate immune response, which could add an additional benefit to targeting pol z in cancer therapies.

Automated summary

The disruption of pol zeta in mammalian cells leads to altered expression of 1,117 transcripts, showing signs of inducing an innate immune response. The increased expression of interferon-stimulated genes in these cells is driven by the cGAS-STING signaling pathway. Additionally, key interferon-stimulated chemokines are elevated in cells with disrupted Rev3l.