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

Aditi; Downing Susanna M.; Schreiner Patrick A.Kwak Young DonLi YangShaw Timothy IRussell Helen R.McKinnon Peter J.

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

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

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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.

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《Neuron》 |2021年第24期|3962-3979|共18页
作者
Aditi; Downing Susanna M.; Schreiner Patrick A.Kwak Young DonLi YangShaw Timothy IRussell Helen R.McKinnon Peter J.;
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作者单位

Dept Cell & Mol Biol,St Jude Childrens Res Hosp;

Ctr Appl Bioinformat,St Jude Childrens Res Hosp;

Moffit Canc Ctr;

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原文格式 PDF
正文语种英语
中图分类神经病学;
关键词
AICARDI-GOUTIERES-SYNDROME; CENTRAL-NERVOUS-SYSTEM; RNASE H2; DNA-DAMAGE; TRANSCRIPTION FACTOR; READ ALIGNMENT; MUTATIONS; TREX1; MICROGLIA; SAMHD1;

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

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