| N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression |
| Lu, T; Chen, AJ; Li, CJ; Li, KY; Wang, S; Zhang, YZ; Yang, BY; Wang, JS ; Gong, QQ; Li, A; Liu, XG; Ma, PC; Mao, BY; Shi, DL; Shao, M
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| 2025
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| 发表期刊 | Nucleic Acids Res.
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| ISSN | 0305-1048
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| 卷号 | 53期号:19 |
| 摘要 | In vitro transcribed messenger RNA (IVT mRNA) has emerged as a pivotal tool in mRNA-based therapies and has been extensively employed in gene function studies and genetic tool applications. However, the IVT process generates double-stranded RNA (dsRNA) by-products that are recognized by dsRNA sensors, triggering innate immune responses. In this study, we comprehensively analyzed the detrimental effects of dsRNA by-products on early zebrafish embryos, revealing that these by-products induce cell necrosis and delay maternal-zygotic transition (MZT) by reducing global translation efficiency via Prkra (Protein Activator Of Interferon Induced Protein Kinase; also called PACT in mammals), a dsRNA sensor recently identified in pluripotent cells. Importantly, we demonstrate that N1-methylpseudouridine (m1 Psi) modification of IVT mRNAs effectively mitigates these adverse effects, as m1 Psi-modified dsRNAs exhibit significantly lower binding affinity to the Prkra dimer. Our findings underscore a previously overlooked challenge in the use of IVT mRNA in early embryos and offer a robust solution to enhance the fidelity of mRNA applications. Furthermore, we elucidate that m1 Psi modification minimizes the dsRNA-induced stress response in pluripotent cells through a distinct mechanism. |
| 收录类别 | SCIE
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| 语种 | 英语
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| 文献类型 | 期刊论文
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| 条目标识符 | http://ir.kiz.ac.cn/handle/152453/14779
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| 专题 | 科研部门_发育生物学（毛炳宇）
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推荐引用方式
GB/T 7714 |
Lu, T,Chen, AJ,Li, CJ,et al. N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression[J]. Nucleic Acids Res.,2025,53(19).
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| APA |
Lu, T.,Chen, AJ.,Li, CJ.,Li, KY.,Wang, S.,...&Shao, M.(2025).N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression.Nucleic Acids Res.,53(19).
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| MLA |
Lu, T,et al."N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression".Nucleic Acids Res. 53.19(2025).
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