ISG15: A link between innate immune signaling, DNA replication, and genome stability

Wardlaw, Christopher P.; Petrini, John H.J.

doi:10.1002/bies.202300042

Cited by 6 publications

(3 citation statements)

References 138 publications

(238 reference statements)

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“…Among these, OAS1 also amplifies the type I IFN pathway and expression of genes that promote immune evasion ( 49 ). In addition, ISG15 links the DNA damage response to regulation of innate immunity ( 50 ). Along these lines, we found that MUC1-C regulates expression of guanylate-binding protein 1 (GBP1), which is activated by chronic inflammation and confers treatment resistance (refs.…”

Section: Resultsmentioning

confidence: 99%

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

Nakashoji,

Haratake,

Bhattacharya

et al. 2024

Cancer Research Communications

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The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCCs). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCCs). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and interferon (IFN) regulatory factors, and (iii) downstream IFN-stimulated genes (ISGs). MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by scRNA-seq analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression.

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Section: Resultsmentioning

confidence: 99%

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

Nakashoji,

Haratake,

Bhattacharya

et al. 2024

Cancer Research Communications

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“…Engagement of such structures leads to activation of an ISG transcriptional program that culminates in the modulation of chromatin states and replication fork stability. In effect, the model suggests that this circuitry, which evolved as an antiviral mechanism has been coopted to effect surveillance of the replication fork 64 (Fig.8F).…”

Section: Discussionmentioning

confidence: 99%

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Wang,

Canasto-Chibuque,

Kim

et al. 2023

Preprint

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The Mre11 complex (comprising Mre11, Rad50, Nbs1) is integral to the maintenance of genome stability. We previously showed that a hypomorphicMre11mutant mouse strain (Mre11ATLD1/ATLD1) was highly susceptible to oncogene induced breast cancer. Here we used a mammary organoid system to examine which Mre11 dependent responses are tumor suppressive. We found thatMre11ATLD1/ATLD1organoids exhibited an elevated interferon stimulated gene (ISG) signature and sustained changes in chromatin accessibility. ThisMre11ATLD1/ATLD1phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation ofIfi205inMre11ATLD1/ATLD1organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed inWT. Implantation ofMre11ATLD1/ATLD1organoids and activation of oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implantedIfi205-/-Mre11ATLD1/ATLD1organoids. These data reveal a connection between innate immune signaling and tumor suppression in mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to tonic innate immune transcriptional programs.

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“…Additionally, the MRN complex regulates fork progression, altering the protein landscape on nascent DNA by a cGAS-STING-TbK1 pathway-dependent modulation of Interferon stimulated gene 15 (ISG15) [32,33].…”

Section: Mrn Complex In Dsbs and Replication Stress Handlingmentioning

confidence: 99%

The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

Petroni,

La Monica,

Fabretti

et al. 2023

Cancers

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Hypomorphic mutations in MRN complex genes are frequently found in cancer, supporting their role as oncosuppressors. However, unlike canonical oncosuppressors, MRN proteins are often overexpressed in tumor tissues, where they actively work to counteract DSBs induced by both oncogene-dependent RS and radio-chemotherapy. Moreover, at the same time, MRN genes are also essential genes, since the constitutive KO of each component leads to embryonic lethality. Therefore, even though it is paradoxical, MRN genes may work as oncosuppressive, oncopromoting, and essential genes. In this review, we discussed how alterations in the MRN complex impact the physiopathology of cancer, in light of our recent discoveries on the gene–dosage-dependent effect of NBS1 in Medulloblastoma. These updates aim to understand whether MRN complex can be realistically used as a prognostic/predictive marker and/or as a therapeutic target for the treatment of cancer patients in the future.

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ISG15: A link between innate immune signaling, DNA replication, and genome stability

Cited by 6 publications

References 138 publications

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

Identification of Muc1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

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