Linking DNA damage and innate immunity, relevant to autoinflammatory disease and cancer

Aicardi-Goutières syndrome (AGS) is a heritable autoinflammatory disorder mimicking in utero viral infection of the brain. Mutations for this disease have been identified in genes with a variety of functions in nucleic acid metabolism; this includes the three subunits of the ribonuclease (RNase) H2 complex. Because nucleic acids are potent activators of innate immunity, which normally provides resistance against viral infection, it is thought that in AGS aberrant nucleic acids stimulate a chronic and inappropriate innate immune response.

We have shown that RNase H2 is an essential enzyme, which removes misincorporated ribonucleotides from DNA and prevents genome instability. cGAS is an important sensor of cytoplasmic DNA, central to activation of an innate immune response upon viral infection and after DNA damage. Our recent work shows that the latter involves the detection of micronuclei, discrete structures formed during mitosis when whole or fragmented chromosomes are excluded from daughter nuclei. Micronuclei frequently form in cancer cells and genome instability is a key driver of neoplasia. Our findings are therefore relevant to both autoinflammatory disease and carcinogenesis.