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eccDNAs are apoptotic products with high innate immunostimulatory activity
Nature ( IF 64.8 ) Pub Date : 2021-10-20 , DOI: 10.1038/s41586-021-04009-w
Yuangao Wang 1, 2 , Meng Wang 1, 2 , Mohamed Nadhir Djekidel 1, 2 , Huan Chen 1, 2 , Di Liu 3, 4 , Frederick W Alt 1, 2, 5 , Yi Zhang 1, 2, 5, 6
Affiliation  

Extrachromosomal circular DNA elements (eccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species1,2. However, their biogenesis and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs map across the entire genome in a close to random manner, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistent with this idea, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a manner that is independent of eccDNA sequence but dependent on eccDNA circularity and the cytosolic DNA sensor Sting. Collectively, our study not only revealed the origin, biogenesis and immunostimulant function of eccDNAs but also uncovered their sensing pathway and potential clinical implications in immune response.



中文翻译:

eccDNA 是具有高先天免疫刺激活性的凋亡产物

染色体外环状 DNA 元件 (eccDNA) 已在文献中描述了几十年,并且因其在不同物种中的广泛存在而闻名1,2. 然而,它们的生物发生和功能在很大程度上是未知的。通过开发一种新的环状 DNA 富集方法,我们在这里使用纳米孔测序纯化和测序了全长 eccDNA。我们发现 eccDNA 以接近随机的方式映射整个基因组,表明基因组 DNA 片段随机连接的生物发生机制。与这个想法一致,我们发现细胞凋亡诱导剂可以增加 eccDNA 的生成,这取决于凋亡 DNA 片段化,然后通过 DNA 连接酶 3 连接。重要的是,我们证明了 eccDNA 可以以独立于 eccDNA 的方式作为有效的先天免疫刺激剂发挥作用序列但取决于 eccDNA 循环性和细胞溶质 DNA 传感器 Sting。总的来说,我们的研究不仅揭示了起源,

更新日期:2021-10-20
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