@article{8e4dfa9ff10d4a4e9dea511d724936db,
title = "Disruption of DNA polymerase ζ engages an innate immune response",
abstract = "In mammalian cells, specialized DNA polymerase ζ (pol ζ) 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 ζ-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 ζ-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 ζ may simultaneously increase sensitivity to genotoxins and potentially engage parts of the innate immune response, which could add an additional benefit to targeting pol ζ in cancer therapies. Martin et al. show that disruption of the catalytic subunit of DNA polymerase ζ, Rev3l, results in the accumulation of DNA damage and increased expression of interferon-stimulated genes. The cGAS-STING pathway, part of the innate immune system that responds to genomic stress, drives this expression signature in pol ζ-deficient cells.",
keywords = "DNA repair, cGAS, genomic instability, transcription",
author = "Martin, {Sara K.} and Junya Tomida and Wood, {Richard D.}",
note = "Funding Information: We thank Sarita Bhetawal and Megan Lowery for assistance with cell culture and advice. We thank Dr. Yue Lu, Dr. Bin Liu, and Kevin Lin for invaluable assistance with the RNA expression data analysis, and Dr. Manu Sebastian, Jimi Lynn Young, and Carlos Perez for in situ hybridization. We are grateful to Winnie Cheng for assistance with the micronuclei experiments. We thank Dr. Wei Yang (NIH) for the gift of the TR4-2 cDNA. Funding was provided by National Institutes of Health grant no. CA193124 , Department of Defense grant no. W81XWH-17-10239 , and the J. Ralph Meadows Chair in Carcinogenesis Research to R.D.W. S.K.M. was supported by a CPRIT Research Training Grant award ( RP170067 ). We thank the cores at The University of Texas MD Anderson Cancer Center in the Department of Epigenetics and Molecular Carcinogenesis that contributed to our data collection. RNA sequencing (Next Generation Sequencing Core) and quantitative PCR were supported by CPRIT grants RP120348 and RP170002 . In situ hybridization performed by the Research Histology, Pathology, and Imaging Core was supported by P30 CA16672-39 DHHS/NCI Cancer Center Support Grant. Funding Information: We thank Sarita Bhetawal and Megan Lowery for assistance with cell culture and advice. We thank Dr. Yue Lu, Dr. Bin Liu, and Kevin Lin for invaluable assistance with the RNA expression data analysis, and Dr. Manu Sebastian, Jimi Lynn Young, and Carlos Perez for in situ hybridization. We are grateful to Winnie Cheng for assistance with the micronuclei experiments. We thank Dr. Wei Yang (NIH) for the gift of the TR4-2 cDNA. Funding was provided by National Institutes of Health grant no. CA193124, Department of Defense grant no. W81XWH-17-10239, and the J. Ralph Meadows Chair in Carcinogenesis Research to R.D.W. S.K.M. was supported by a CPRIT Research Training Grant award (RP170067). We thank the cores at The University of Texas MD Anderson Cancer Center in the Department of Epigenetics and Molecular Carcinogenesis that contributed to our data collection. RNA sequencing (Next Generation Sequencing Core) and quantitative PCR were supported by CPRIT grants RP120348 and RP170002. In situ hybridization performed by the Research Histology, Pathology, and Imaging Core was supported by P30 CA16672-39 DHHS/NCI Cancer Center Support Grant. S.K.M. designed and performed the experiments, led the data interpretation, and drafted the manuscript. J.T. established the complemented cell line pairs and assisted with the manuscript. R.D.W. assisted with the experimental design, data interpretation, and writing. R.D.W. is a scientific advisor for Repare Therapeutics and a shareholder. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = feb,
day = "23",
doi = "10.1016/j.celrep.2021.108775",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}