The innate immune system is able to detect the presence of DNA in the cytosol of infected cells as pathogen-associated molecular pattern (PAMP), for instance during infection with DNA viruses. Cytosolic DNA can also be detected as damage- or danger-associated molecular pattern (DAMP), when cytosolic micronuclei form after DNA damage. Cytosolic DNA is detected by the DNA sensor cGAS and its adaptor protein STING. In human cells, the DNA binding protein IFI16 co-operates with cGAS in the detection of cytosolic DNA. We have recently discovered that IFI16 also detects DNA damage and replication stress in the nucleus, where it signals to the innate immune adaptor STING in a cGAS-independent manner, and long before the appearance of micronuclei. This leads to a different mode of STING activation, and ultimately the production of a different cytokine and chemokine expression profile. The molecular mechanisms that link replication stress, DNA damage and innate immunity may play a key role in shaping the tumour microenvironment during immunosurveillance and inflammation-driven tumour progression.
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Dr Leonie Unterholzner holds a BSc in Biochemistry from the University of York, and an MSc from Imperial College London. Following two years of working as volunteer science teacher in Rwanda, she completed her PhD at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. She obtained a Marie Curie IntraEuropean Fellowship to start her postdoctoral work at Trinity College Dublin, where she developed an interest in innate immunity and viral immune evasion. Leonie started her independent research group in 2013 at the University of Dudee, funded by an MRC Career Development Award. She is currently a Senior Lecturer at Lancaster University where her lab investigates how the innate immune system detects the presence of foreign or damaged DNA inside cells, and how pathogens subvert these detection mechanisms.
