ArticleNucleic acids research2024
Loss of the DNA repair protein, polynucleotide kinase/phosphatase, activates the type 1 interferon response independent of ionizing radiation.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Integrative multi-omics analysis identifies endocrine-disrupting chemical-related molecular mechanisms in migraine.The journal of headache and pain · 2026Article
- Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.NAR cancer · 2026Article
- Deficiency ofZoological research · 2026Article
- Impact of oxidative stress on malignant tumor progression and emerging therapeutic strategies.Frontiers in molecular biosciences · 2026Review
- L3MBTL2 as a novel therapeutic target for trigeminal neuralgia: evidence from integrated TWAS, multi-tissue MR, and experimental validation.The journal of headache and pain · 2025Article
- Dirty Ends: Formation, Repair, and Biological Relevance of Non-Canonical DNA Terminal Structures.Genes · 2025Review
- Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.bioRxiv : the preprint server for biology · 2025Article
- Mitochondrial metabolism and cancer therapeutic innovation.Signal transduction and targeted therapy · 2025Review
- Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders.Journal of neuroinflammation · 2025Review
- Plasma pQTL and brain eQTL integration identifies PNKP as a therapeutic target and reveals mechanistic insights into migraine pathophysiology.The journal of headache and pain · 2024Article
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Authors and funding
3 authors.
Funding
Abstract
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.
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