Hongzhan Xu, Jing Ye, Kui-Xing Zhang, Qingxi Hu, Tongxiao Cui, Chong Tong, Mengqi Wang, Huichao Geng, Kun-Ming Shui, Yan Sun, Jian Wang, Xiaomeng Hou, Kai Zhang, Ran Xie, Yafei Yin, Nan Chen, Jia-Yu Chen
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引用次数: 0
摘要
当第三条 DNA 链缠绕在 DNA 主沟上时形成的三重 DNA 结构是关键的分子调控因子和基因组威胁。然而,人们对支配三重 DNA 动态的调控网络仍然知之甚少。在这里,我们通过活细胞中的化学蛋白质组分析,揭示了与三重 DNA 相互作用的蛋白质的结合和功能谱系。我们开发了一种化学探针,它对三重 DNA 具有特殊的特异性。通过采用共结合介导的近距离捕获策略,我们富集了三重 DNA 相互作用组,用于定量蛋白质组学分析。这样就能鉴定出与三重 DNA 相互作用的蛋白质综合列表,这些蛋白质在其原生染色质环境中具有不同的结合特性和调控机制。作为示范,我们验证了 DDX3X 是一种不依赖 ATP 的三重 DNA 螺旋酶,能解开带有 5′悬垂的底物,防止 DNA 损伤。总之,我们的研究为探索三重 DNA 的生物学和转化潜力提供了宝贵的资源。
Chemoproteomic profiling unveils binding and functional diversity of endogenous proteins that interact with endogenous triplex DNA
Triplex DNA structures, formed when a third DNA strand wraps around the major groove of DNA, are key molecular regulators and genomic threats. However, the regulatory network governing triplex DNA dynamics remains poorly understood. Here we reveal the binding and functional repertoire of proteins that interact with triplex DNA through chemoproteomic profiling in living cells. We develop a chemical probe that exhibits exceptional specificity towards triplex DNA. By employing a co-binding-mediated proximity capture strategy, we enrich triplex DNA interactome for quantitative proteomics analysis. This enables the identification of a comprehensive list of proteins that interact with triplex DNA, characterized by diverse binding properties and regulatory mechanisms in their native chromatin context. As a demonstration, we validate DDX3X as an ATP-independent triplex DNA helicase to unwind substrates with a 5′ overhang to prevent DNA damage. Overall, our study provides a valuable resource for exploring the biology and translational potential of triplex DNA.
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