Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair.
Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair.
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独立于I型干扰素信号的基因组不稳定性驱动由受损的核糖核苷酸切除修复引起的神经病理。
DOI：
10.1016/j.neuron.2021.09.040
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发表时间：
2021-12-15
期刊：
影响因子：
16.2
通讯作者：
McKinnon PJ
中科院分区：
文献类型：
--
作者：
Aditi;Downing SM;Schreiner PA;Kwak YD;Li Y;Shaw TI;Russell HR;McKinnon PJ
Aicardi-Gtières综合征(AGS)是一种以神经发育缺陷、I型干扰素信号上调和神经炎症为特征的单基因I型干扰素病。在核酸代谢中起作用的基因突变，包括RNaseH2与AGS有关。核糖核酸酶H2(RNaseH2)是一种基因组监控因子，通过去除复制DNA中的核糖核苷酸，对DNA完整性至关重要。在这里，我们证明了RNaseH2对于神经发生和避免干扰素反应基因的激活和神经炎症是必要的。RNASH2B失活后的小脑缺陷可以通过p53而不是cGAS缺失来修复，这表明DNA损伤信号而不是神经炎症是神经病理的原因。ATM和RNaseH2的同时失活进一步影响小脑发育，导致共济失调，这依赖于非同源末端连接(NHEJ)的异常激活。ATM的丢失还显著加剧了cGAS依赖的I型干扰素信号。因此，在这类神经发育/神经炎性疾病中，依赖DNA损伤的信号而不是I型干扰素信号是神经退行性变的基础。RNaseH2的突变与艾卡迪-古蒂埃综合征有关。阿迪提等人。等人的研究表明，RNaseH2对于神经发生和避免干扰素反应基因的激活是必要的。这些缺陷可以被p53修复，但不能被cGAS失活，这表明DNA损伤信号，而不是神经炎症，在这类疾病中解释了神经病理。
Aicardi-Goutières 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 impacted 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. Mutations in RNASEH2 are linked to Aicardi-Goutières syndrome. Aditi et. al., show that RNASEH2 is necessary for neurogenesis and to avoid activation of interferon-responsive genes. These defects are rescued by p53 but not cGAS inactivation, suggesting that DNA damage signaling, not neuroinflammation, accounts for neuropathology in this class of disease.
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影响因子：
7.3
作者：
Bartsch K;Damme M;Regen T;Becker L;Garrett L;Hölter SM;Knittler K;Borowski C;Waisman A;Glatzel M;Fuchs H;Gailus-Durner V;Hrabe de Angelis M;Rabe B
通讯作者：
Rabe B
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.7
作者：
Perrino, Fred W.;Harvey, Scott;Shaban, Nadine M.;Hollis, Thomas
通讯作者：
Hollis, Thomas
影响因子：
6.2
作者：
Gao, Tianwen;Jernigan, Janna;Rangaraju, Srikant
通讯作者：
Rangaraju, Srikant
DOI：
10.1073/pnas.1809682115
发表时间：
2018-12-26
影响因子：
11.1
作者：
Dumitrache, Lavinia C.;Shimada, Mikio;McKinnon, Peter J.
通讯作者：
McKinnon, Peter J.