Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress
Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress
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DOI：
10.1074/jbc.m116.718478
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发表时间：
2016-08-19
影响因子：
4.8
通讯作者：
Raney, Kevin D.
中科院分区：
文献类型：
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作者：
Byrd, Alicia K.;Zybailov, Boris L.;Raney, Kevin D.
细胞参与许多信号通路，以响应氧化应激，共同修复大分子损伤或指导细胞凋亡。作为DNA损伤的结果，线粒体DNA或核DNA已被证明进入细胞质，在那里它结合到DNA传感器，这反过来启动信号级联。在这里，我们报告的数据，支持一种新的信号通路在响应氧化应激介导的特定的富含鸟嘌呤的序列，可以折叠成G-四链体DNA（G4 DNA）。在氧化应激反应中，我们证明了能够形成G4 DNA的序列在细胞质中的水平不断增加，并参与应激颗粒的组装。已知与细胞质中的内源性G4 DNA结合的鉴定的蛋白质调节mRNA翻译并参与应激颗粒形成。与这些发现一致，已知应激颗粒形成在氧化应激期间调节mRNA翻译。我们提出了一个信号通路，使细胞可以迅速响应氧化应激引起的DNA损伤。从受损的基因组DNA中切除的富含鸟嘌呤的序列被提出进入细胞质，在那里它们可以通过应激颗粒的形成来调节翻译。这一新提出的G4 DNA的作用为为什么这些序列在人类基因组中普遍存在提供了额外的分子解释。
Cells engage numerous signaling pathways in response to oxidative stress that together repair macromolecular damage or direct the cell toward apoptosis. As a result of DNA damage, mitochondrial DNA or nuclear DNA has been shown to enter the cytoplasm where it binds to DNA sensors, which in turn initiate signaling cascades. Here we report data that support a novel signaling pathway in response to oxidative stress mediated by specific guanine-rich sequences that can fold into G-quadruplex DNA (G4DNA). In response to oxidative stress, we demonstrate that sequences capable of forming G4DNA appear at increasing levels in the cytoplasm and participate in assembly of stress granules. Identified proteins that bind to endogenous G4DNA in the cytoplasm are known to modulate mRNA translation and participate in stress granule formation. Consistent with these findings, stress granule formation is known to regulate mRNA translation during oxidative stress. We propose a signaling pathway whereby cells can rapidly respond to DNA damage caused by oxidative stress. Guanine-rich sequences that are excised from damaged genomic DNA are proposed to enter the cytoplasm where they can regulate translation through stress granule formation. This newly proposed role for G4DNA provides an additional molecular explanation for why such sequences are prevalent in the human genome.