{
  "abstract": "Background Extrachromosomal double-stranded DNA (dsDNA) activates cGAS-STING-dependent innate immune response. In cancer, aberrant incorporation of non-canonical bases such as deoxyuridine (dU) is frequently observed due to antimetabolite therapy and dysregulated cytidine deaminase activity. However, the impact of dU-containing DNA (dU-DNA) on innate immune sensing is yet to be defined.Methods and Results Here, we found that synthetic dsDNA fragment containing dU (dU-DNA) fails to activate type I interferon (IFN) signaling. Mechanistically, dU-DNA does not bind to key DNA sensors cGAS or IFI16 and effectively blocks downstream activation of both cGAS- and STING-mediated pathways. To explore the physiological relevance of this finding, we generated B16F10 melanoma cells deficient in uracil-DNA glycosylase (UNG), the key enzyme responsible for removing uracil from DNA. Building on our previous work showing that ATR inhibition (ATRi) promotes dU incorporation, we treated WT and UNG-deficient B16F10 cells with ATRi and observed significant reduction in type-1 IFN signalling in UNG deficient cells compared to its wild-type counterpart.Conclusions Together, these findings reveal an unexpected immunosuppressive role for dU-DNA by modulating the cGAS-STING pathway. This study has significant importance in the context of cancer-associated DNA damage, repair deficiencies and treatment to anti-metabolite therapy.",
  "authors": [
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Pinakin Pandya"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Frank P Vendetti"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Sudipta Pathak"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Yunqi Zhang"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, PA, USA"
      ],
      "name": "Reyna Jones"
    },
    {
      "affiliations": [
        "UPMC Hillman Cancer Center, Pittsburgh, PA, USA"
      ],
      "name": "Christopher Bakkenist"
    }
  ],
  "title": "1283 Deoxyuridine-containing dsDNA suppresses cGAS-STING-mediated type i interferon responses",
  "uid": "908622d3-9392-5687-9f74-350543bc31bd"
}