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镜像核苷对人体细胞中DNA复制和转录的影响。

Effects of mirror-image nucleosides on DNA replication and transcription in human cells.

作者信息

Jin Zhaoyang, Wang Yifei, Cui Shuaishuai, He Yujian, Wu Li

机构信息

School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, PR China.

College of Life Sciences, Hebei Normal University, Shijiazhuang, PR China.

出版信息

J Biol Chem. 2025 Feb;301(2):108139. doi: 10.1016/j.jbc.2024.108139. Epub 2024 Dec 26.

DOI:10.1016/j.jbc.2024.108139
PMID:39732173
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11815684/
Abstract

Mirror-image nucleosides, as potential antiviral drugs, can inhibit virus DNA polymerase to prevent virus replication. Conversely, they may be inserted into the DNA strands during DNA replication or transcription processes, leading to mutations that affect genome stability. Accumulation of significant mutation damage in cells may result in cell aging, apoptosis, and even uncontrolled cell division. We have previously explored the efficiency and fidelity of replication across mirror-image nucleosides within Escherichia coli, and this study focuses on human cells. We constructed several plasmid substrates, each carrying a specific mirror-image nucleoside, to investigate their impact on intracellular DNA replication and transcription processes. The results showed that in HepG2 cells, L-adenosine was the most potent substrate in inhibiting cell replication and transcription. L-cytidine exhibited the highest bypass efficiency in both template strands or nontemplate strands and had the most diverse mutation types. We also observed that L-cytidine induced immunoregulation of the JAK-STAT signaling pathway. Therefore, our results provide a theoretical basis for the disruptions caused by mirror-image nucleosides in replication and transcription and give us some understanding that mirror-image nucleoside drugs can cause cytotoxicity.

摘要

镜像核苷作为潜在的抗病毒药物，可以抑制病毒DNA聚合酶以防止病毒复制。相反，它们可能在DNA复制或转录过程中插入DNA链，导致影响基因组稳定性的突变。细胞中大量突变损伤的积累可能导致细胞衰老、凋亡，甚至细胞的无控制分裂。我们之前已经探究了大肠杆菌中跨越镜像核苷进行复制的效率和保真度，而本研究聚焦于人类细胞。我们构建了几个质粒底物，每个都携带一种特定的镜像核苷，以研究它们对细胞内DNA复制和转录过程的影响。结果表明，在HepG2细胞中，L-腺苷是抑制细胞复制和转录最有效的底物。L-胞苷在模板链或非模板链中均表现出最高的绕过效率，并且具有最多样化的突变类型。我们还观察到L-胞苷诱导了JAK-STAT信号通路的免疫调节。因此，我们的结果为镜像核苷在复制和转录中造成的干扰提供了理论基础，并让我们了解到镜像核苷药物会导致细胞毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/aace0fbe792a/figs14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/c10ee11aa75b/gr1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/9c9d9d2315ff/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/892dc1d820cd/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/84d3fabc9efc/figs3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/4d2f37a79562/figs6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/2bf0b7642020/figs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/f9c44a131585/figs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/ff5ec8ce0bd5/figs12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/7ef6393c212f/figs13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/aace0fbe792a/figs14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/c10ee11aa75b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/a343db30540c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/f2698326a4ad/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/9f40e7a79dab/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/bdd71fea161f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/fb35aa01e305/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/5545401cbf74/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/9c9d9d2315ff/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/892dc1d820cd/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/84d3fabc9efc/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/afec93363843/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/e06a57947402/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/4d2f37a79562/figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/b26d14718a03/figs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/f3b99d7e753e/figs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/207d7addece3/figs9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/2bf0b7642020/figs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/f9c44a131585/figs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/ff5ec8ce0bd5/figs12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/7ef6393c212f/figs13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b27d/11815684/aace0fbe792a/figs14.jpg

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