Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes

Abstract

Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.

Chronic exposure to Cytolethal Distending Toxin (CDT) promotes a cGAS-dependent type I interferon response

“…However, CdtB from typhoid toxin rather promotes an anti-inflammatory environment in infected mice [30], which might be a consequence of proinflammatory response inhibition by type I IFN [32]. On the other hand, many ISGs, and notably those addressed in the present study, belong to the Interferon-Related DNA Damage Resistance Signature (IRDS) group, and their upregulation in cancer cells is associated with resistance to DNA damage, suppression of T cell toxicity and enhanced tumor survival [54]. Finally, modulation of the immune environment by CDT upon infection may vary with tissue or even cell type, as evidenced with cGAS downregulation in HCECs.…”

Structural determinants of peptide-dependent TAP1-TAP2 transit passage targeted by viral proteins and altered by cancer-associated mutations

“…The type I (IFN-α and IFN-β) and type II (IFN-γ) IFNs are key cytokines in the antiviral response. IFN-β is secreted from most cells in response to viral infection involving dendritic cells and many other cell types in the body [40] , [42] . At later stages of immune response, IFN-γ is secreted from T-cells and other immune cells [40] .…”

“…At later stages of immune response, IFN-γ is secreted from T-cells and other immune cells [40] . The interferons strongly affect cellular metabolism and gene expression, including MHC-I as well as MHC-II molecules and also upregulate antigen processing and presentation components such as; ER aminopeptidase 1/2 and the TAP transporters [8] , [40] , [42] , [43] , [44] , [45] , [46] . Moreover, when cells are treated with IFN-γ, the regular proteasomes are replaced by the immunoproteasomes [46] .…”

Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

“…Previous studies have shown that resistance of some cancers to chemotherapy and/or radiation therapy could be associated with so-called IRDS. 25 , 26 , 27 , 28 Although the exact mechanism of increased resistance of GR cell lines to gemcitabine is beyond the scope of this study, and the exact role of IRDS in resistance of some cancers to chemotherapy and/or radiation therapy is still unclear, we examined whether the ISGs overexpressed in response to VSV are also upregulated in GR cells after treatment with gemcitabine. Cells were either mock treated, infected with VSV-ΔM51 at MOI 0.01, or treated with gemcitabine at a concentration of either 5 μM or 0.1 μM.…”

“…We also show that the increased resistance of these cell lines to both gemcitabine and tested viruses correlated with upregulated levels of a subset of ISGs, resembling the interferon-related DNA damage resistance signature (IRDS), often associated with resistance of cancer cells to chemotherapy and/or radiation therapy. 25 , 26 , 27 , 28 Analysis of 10 different PDAC cell lines showed that, although no statistically significant correlation between chemoresistance and resistance to VSV was observed in all 10 tested PDAC cell lines, 4 PDAC cell lines most resistant to VSV were also highly resistant to gemcitabine. Moreover, the same 4 cell lines all displayed IRDS-like expression in our previous reports.…”