Loss of the DNA repair protein, polynucleotide kinase/phosphatase, activates the type 1 interferon response independent of ionizing radiation.
| Autor: | Kate WD; Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada., Fanta M; Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada., Weinfeld M; Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. |
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| Jazyk: | angličtina |
| Zdroj: | Nucleic acids research [Nucleic Acids Res] 2024 Sep 09; Vol. 52 (16), pp. 9630-9653. |
| DOI: | 10.1093/nar/gkae654 |
| Abstrakt: | DNA damage has been implicated in the stimulation of the type 1 interferon (T1IFN) response. Here, we show that downregulation of the DNA repair protein, polynucleotide kinase/phosphatase (PNKP), in a variety of cell lines causes robust phosphorylation of STAT1, upregulation of interferon-stimulated genes and persistent accumulation of cytosolic DNA, all of which are indicators for the activation of the T1IFN response. Furthermore, this did not require damage induction by ionizing radiation. Instead, our data revealed that production of reactive oxygen species (ROS) synergises with PNKP loss to potentiate the T1IFN response, and that loss of PNKP significantly compromises mitochondrial DNA (mtDNA) integrity. Depletion of mtDNA or treatment of PNKP-depleted cells with ROS scavengers abrogated the T1IFN response, implicating mtDNA as a significant source of the cytosolic DNA required to potentiate the T1IFN response. The STING signalling pathway is responsible for the observed increase in the pro-inflammatory gene signature in PNKP-depleted cells. While the response was dependent on ZBP1, cGAS only contributed to the response in some cell lines. Our data have implications for cancer therapy, since PNKP inhibitors would have the potential to stimulate the immune response, and also to the neurological disorders associated with PNKP mutation. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.) |
| Databáze: | MEDLINE |
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