Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair

Aicardi-Goutieres syndrome (AGS) is a monogenic type I interferonopathy characterized by neurodevelopmental defects and upregulation of type I interferon signaling and neuroinflammation. Mutations in genes that function in nucleic acid metabolism, including RNASEH2, are linked to AGS. Ribonuclease H2 (RNASEH2) is a genome surveillance factor critical for DNA integrity by removing ribonucleotides incorporated into replicating DNA. Here we show that RNASEH2 is necessary for neurogenesis and to avoid activation of interferon-responsive genes and neuroinflammation. Cerebellar defects after RNASEH2B inactivation are rescued by p53 but not cGAS deletion, suggesting that DNA damage signaling, not neuroinflammation, accounts for neuropathology. Coincident inactivation of Atm and Rnaseh2 further affected cerebellar development causing ataxia, which was dependent upon aberrant activation of non-homologous end-joining (NHEJ). The loss of ATM also markedly exacerbates cGAS-dependent type I interferon signaling. Thus, DNA damage-dependent signaling rather than type I interferon signaling underlies neurodegeneration in this class of neurodevelopmental/neuroinflammatory disease.

Automated summary

Aicardi-Goutieres syndrome (AGS) is a monogenic disorder characterized by defects in neurodevelopment and inflammation due to mutations in genes related to nucleic acid metabolism. RNASEH2 plays a crucial role in maintaining DNA integrity and neurogenesis, preventing activation of interferon-responsive genes and neuroinflammation. The pathogenesis of neurodegeneration in AGS involves DNA damage-dependent signaling rather than type I interferon signaling.