Disruption of DNA polymerase ζ engages an innate immune response

Martin, Sara K.; Tomida, Junya; Wood, Richard D.

doi:10.1016/j.celrep.2021.108775

Cited by 15 publications

(4 citation statements)

References 49 publications

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“… 18–22 For example, polymerase ζ-deficient cells accumulated micronuclei and induced expression of IFN-stimulated genes in a cGAS- and STING-dependent manner. 23 In response to acute BRCA2 abrogation, tumor cells accumulated micronuclei and limited proliferation by G1 cell cycle arrest. As the cells adapted to chronic BRCA2 loss, they re-entered the cell cycle with a concomitant upregulation of IFN-stimulated genes that was dependent on STING and STAT1.…”

Section: Discussionmentioning

confidence: 99%

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Higgs

Bao

Hatogai

et al. 2022

J Immunother Cancer

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BackgroundA T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.MethodsRNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy.ResultsAmong the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2+ tumor cells and CD8+ T cells. Additionally, melanomas with high MSH2+ tumor cell numbers were largely non-responders to anti-PD-1 therapy.ConclusionsIncreased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Higgs

Bao

Hatogai

et al. 2022

J Immunother Cancer

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“…Interferon Alpha Inducible Protein 27 (IFI27) expression sensitizes cells to apoptotic stimuli [31], which may help the intestinal epithelium to repel astrovirusinfected cells. The dysregulation of REV3L the catalytic subunit of DNA polymerase ζ engages the innate immune response with potential antiviral consequences [32]. However, additional studies are needed to test these hypotheses.…”

Section: Distinct Degs and Biological Processes (Bp) Were Also Noted For Each Enteric Virusmentioning

confidence: 99%

Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses

Cieza

Golob

Colacino

et al. 2021

Viruses

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Acute gastroenteritis (AGE) has a significant disease burden on society. Noroviruses, rotaviruses, and astroviruses are important viral causes of AGE but are relatively understudied enteric pathogens. Recent developments in novel biomimetic human models of enteric disease are opening new possibilities for studying human-specific host–microbe interactions. Human intestinal enteroids (HIE), which are epithelium-only intestinal organoids derived from stem cells isolated from human intestinal biopsy tissues, have been successfully used to culture representative norovirus, rotavirus, and astrovirus strains. Previous studies investigated host–virus interactions at the intestinal epithelial interface by individually profiling the epithelial transcriptional response to a member of each virus family by RNA sequencing (RNA-seq). Despite differences in the tissue origin, enteric virus used, and hours post infection at which RNA was collected in each data set, the uniform analysis of publicly available datasets identified a conserved epithelial response to virus infection focused around “type I interferon production” and interferon-stimulated genes. Additionally, transcriptional changes specific to only one or two of the enteric viruses were also identified. This study can guide future explorations into common and unique aspects of the host response to virus infections in the human intestinal epithelium and demonstrates the promise of comparative RNA-seq analysis, even if performed under different experimental conditions, to discover universal and virus-specific genes and pathways responsible for antiviral host defense.

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“…The cGAS-STING pathway is a well-characterized pathway, in which cyclic GMP-AMP synthase (cGAS) binds to cytoplasmic DNA and catalyzes the formation of cyclic GMP-AMP (cGAMP), which in turn binds to the adaptor stimulator of interferon genes (STING), leading to the upregulation of inflammation-related genes [ 41 ]. In fact, it has been reported that the loss of Pol ξ, a B-family specialized Pol, induces an innate immune response involving the cGAS-STING pathway [ 42 ]. Inflammatory hyperplasia is induced by ultraviolet (UV) light in mice that express hypomorphic Rev1, which lacks the N-terminal BRCT domain [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase κ suppresses inflammation and inflammation-induced mutagenesis and carcinogenic potential in the colon of mice

et al. 2023

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Background Chronic inflammation induces DNA damage and promotes cell proliferation, thereby increasing the risk of cancer. DNA polymerase κ (Pol κ), involved in translesion DNA synthesis, counteracts mutagenesis induced by inflammation in the colon of mice. In the present study, we examined whether Pol κ suppressed inflammation-induced colon tumorigenesis by treating inactivated Polk knock-in (Polk−/−) mice with dextran sulfate sodium (DSS), an inducer of colon inflammation. Results Male and female Polk−/− and Polk+/+ mice were administered 2% DSS in drinking water for six consecutive days, succeeded via a recovery period of 16 days, followed by 2% DSS for another two days. DSS treatment strongly induced colitis, and the severity of colitis was higher in Polk−/− mice than in Polk+/+ mice. The mice were sacrificed after 19 weeks from the initiation of the first DSS treatment and subjected to pathological examination and mutation analysis. DSS treatment induced colonic dysplasia, and the multiplicity of dysplasia was higher in Polk−/− mice than in Polk+/+mice. Some of the dysplasias in Polk−/− mice exhibited β-catenin-stained nucleus and/or cytoplasm. Mutation frequencies in the gpt reporter gene were increased by DSS treatment in Polk−/− mice, and were higher than those in Polk+/+ mice. Conclusions Pol κ suppresses inflammation and inflammation-induced dysplasia as well as inflammation-induced mutagenesis. The possible mechanisms by which Pol κ suppresses colitis- and colitis-induced dysplasia are discussed.

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Disruption of DNA polymerase ζ engages an innate immune response

Cited by 15 publications

References 49 publications

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration

Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses

DNA polymerase κ suppresses inflammation and inflammation-induced mutagenesis and carcinogenic potential in the colon of mice

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