RNase H2, mutated in Aicardi-Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation.
RNase H2, mutated in Aicardi-Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation.
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DOI：
10.1038/s41467-022-30604-0
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发表时间：
2022-05-26
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
RNase H2是一种在RNA/DNA杂交体中降解RNA的特殊酶，缺乏这种酶会导致严重的神经炎性疾病Aicardi gouti<e:1>综合征（AGS）。然而，AGS的分子机制尚不清楚。在这里，我们发现RNase H2以转录依赖的方式与RNA聚合酶II相互作用，与一个基因子集相关。RNase H2缺失会损害转录，导致r环的积累，r环是RNA/DNA杂交结构和移位的DNA链，主要与短基因和无内含子基因相关。重要的是，积累的r环被XPG和XPF内切酶处理，导致DNA损伤和免疫反应的激活，这是与AGS相关的特征。因此，我们揭示了RNase H2通过维持r环稳态在人类基因转录中的关键作用。我们的研究结果对r -环在AGS发病机制中的作用机制提供了深入的了解。RnaseH2在严重神经炎性疾病Aicardi - gouti<e:1>综合征中发生突变。在这里，作者揭示了RNase H2控制细胞r -环稳态，以促进转录、基因组完整性和预防r -环相关炎症。
RNase H2 is a specialized enzyme that degrades RNA in RNA/DNA hybrids and deficiency of this enzyme causes a severe neuroinflammatory disease, Aicardi Goutières syndrome (AGS). However, the molecular mechanism underlying AGS is still unclear. Here, we show that RNase H2 is associated with a subset of genes, in a transcription-dependent manner where it interacts with RNA Polymerase II. RNase H2 depletion impairs transcription leading to accumulation of R-loops, structures that comprise RNA/DNA hybrids and a displaced DNA strand, mainly associated with short and intronless genes. Importantly, accumulated R-loops are processed by XPG and XPF endonucleases which leads to DNA damage and activation of the immune response, features associated with AGS. Consequently, we uncover a key role for RNase H2 in the transcription of human genes by maintaining R-loop homeostasis. Our results provide insight into the mechanistic contribution of R-loops to AGS pathogenesis. RnaseH2 is mutated in severe neuro-inflammatory disorder Aicardi‐Goutières syndrome. Here the authors reveal that RNase H2 controls cellular R-loop homeostasis to promote transcription, genome integrity and prevent R-loop-associated inflammation.
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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
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Rabe B
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影响因子：
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作者：
Arana, Mercedes E.;Kerns, Robnet T.;Wharey, Laura;Gerrish, Kevin E.;Bushel, Pierre R.;Kunkel, Thomas A.
通讯作者：
Kunkel, Thomas A.
影响因子：
14.9
作者：
Chon H;Sparks JL;Rychlik M;Nowotny M;Burgers PM;Crouch RJ;Cerritelli SM
通讯作者：
Cerritelli SM
影响因子：
3.3
作者：
Conover, Hailey N.;Lujan, Scott A.;Argueso, Juan Lucas
通讯作者：
Argueso, Juan Lucas
影响因子：
4.6
作者：
Epshtein, Anastasiya;Potenski, Catherine J.;Klein, Hannah L.
通讯作者：
Klein, Hannah L.