Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells.
Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells.
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先天免疫介质STING调节人类细胞中停滞分叉处的新生DNA代谢。
DOI：
10.3389/fmolb.2022.1048726
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
背景资料：cGAS/STING途径是对外源DNA的先天免疫应答的一部分，可以被细胞自身的DNA激活，所述DNA由基因组的加工产生，包括在被阻止的复制叉处的新生DNA的降解，其可以在癌细胞中上调。最近的证据提出了一种可能性，即cGAS/STING途径也可能调节触发它的过程，例如，DNA损伤修复或处理停滞的叉子。 研究方法：我们通过耗尽或重新表达STING来操纵人类细胞中的STING水平，并使用微流体辅助复制跟踪分析（或玛尔塔）、DNA纤维测定以及新生DNA的免疫沉淀（或iPOND）来评估STING对复制的影响。我们还评估了STING亚细胞分布及其激活能力。 结果如下：STING抑制的耗尽及其在STING缺陷型癌细胞中的重新表达上调了在停滞的复制叉处新生DNA的降解。复制叉停滞伴随着STING途径激活，并且不激活该途径的STING突变体未能上调新生DNA降解。STING对降解的作用需要cGAS，但这种要求可以通过用STING激动剂处理细胞来绕过。与具有野生型STING的细胞相比，表达失活STING的细胞在被捕叉的亲本和新生DNA上具有降低的RPA水平和降低的CHK 1活化。STING还影响了细胞系亚组中未受干扰的分叉进展。STING主要分布于核内，富含染色质和核膜结构成分，并与复制叉和复制后染色质结合。 结论：我们的数据强调STING作为停滞复制叉完整性的决定因素，从而揭示了复制应激和先天免疫反应之间的新联系。
Background: The cGAS/STING pathway, part of the innate immune response to foreign DNA, can be activated by cell’s own DNA arising from the processing of the genome, including the degradation of nascent DNA at arrested replication forks, which can be upregulated in cancer cells. Recent evidence raises a possibility that the cGAS/STING pathway may also modulate the very processes that trigger it, e.g., DNA damage repair or processing of stalled forks. Methods: We manipulated STING levels in human cells by depleting or re-expressing it, and assessed the effects of STING on replication using microfluidics-assisted replication track analysis, or maRTA, a DNA fiber assay, as well as immuno-precipitation of nascent DNA, or iPOND. We also assessed STING subcellular distribution and its ability to activate. Results: Depletion of STING suppressed and its re-expression in STING-deficient cancer cells upregulated the degradation of nascent DNA at arrested replication forks. Replication fork arrest was accompanied by the STING pathway activation, and a STING mutant that does not activate the pathway failed to upregulate nascent DNA degradation. cGAS was required for STING’s effect on degradation, but this requirement could be bypassed by treating cells with a STING agonist. Cells expressing inactive STING had a reduced level of RPA on parental and nascent DNA of arrested forks and a reduced CHK1 activation compared to cells with the wild type STING. STING also affected unperturbed fork progression in a subset of cell lines. STING fractionated to the nuclear fractions enriched for structural components of chromatin and nuclear envelope, and furthermore, it associated with the chromatin of arrested replication forks as well as post-replicative chromatin. Conclusion: Our data highlight STING as a determinant of stalled replication fork integrity, thus revealing a novel connection between the replication stress and innate immune responses.
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影响因子：
11.4
作者：
Betous, Remy;Pillaire, Marie-Jeanne;Pierini, Laura;van der Laan, Siem;Recolin, Benedicte;Ohl-Seguy, Emma;Guo, Caixia;Niimi, Naoko;Gruz, Petr;Nohmi, Takehiko;Friedberg, Errol;Cazaux, Christophe;Maiorano, Domenico;Hoffmann, Jean-Sebastien
通讯作者：
Hoffmann, Jean-Sebastien
ATM 和 IFI16 对 DNA 传感适配器 STING 的非规范激活可在核 DNA 损伤后介导 NF-κB 信号转导。
影响因子：
16
作者：
Dunphy G;Flannery SM;Almine JF;Connolly DJ;Paulus C;Jønsson KL;Jakobsen MR;Nevels MM;Bowie AG;Unterholzner L
通讯作者：
Unterholzner L
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D
DOI：
10.1073/pnas.1801213115
发表时间：
2018-04-17
影响因子：
11.1
作者：
Chen, Shuliang;Bonifati, Serena;Wu, Li
通讯作者：
Wu, Li