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首页> 外文期刊>Journal of Photochemistry and Photobiology, B. Biology: Official Journal of the European Society for Photobiology >Transfection of pseudouridine-modified mRNA encoding CPD-photolyase leads to repair of DNA damage in human keratinocytes: A new approach with future therapeutic potential
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Transfection of pseudouridine-modified mRNA encoding CPD-photolyase leads to repair of DNA damage in human keratinocytes: A new approach with future therapeutic potential

机译：转染编码CPD-光裂解酶的假尿苷修饰的mRNA可导致人角质形成细胞DNA损伤的修复：具有潜在治疗潜力的新方法

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UVB irradiation induces harmful photochemical reactions, including formation of Cyclobutane Pyrimi-dine Dimers (CPDs) in DNA. Accumulation of unrepaired CPD lesions causes inflammation, premature ageing and skin cancer. Photolyases are DNA repair enzymes that can rapidly restore DNA integrity in a light-dependent process called photoreactivation, but these enzymes are absent in humans. Here, we present a novel mRNA-based gene therapy method that directs synthesis of a marsupial, Potorous tri-dactylus, CPD-photolyase in cultured human keratinocytes. Pseudouridine was incorporated during in vitro transcription to make the mRNA non-immunogenic and highly translatable. Keratinocytes trans-fected with lipofectamine-complexed mRNA expressed photolyase in the nuclei for at least 2 days. Exposing photolyase mRNA-transfected cells to UVB irradiation resulted in significantly less CPD in those cells that were also treated with photoreactivating light, which is required for photolyase activity. The functional photolyase also diminished other UVB-mediated effects, including induction of IL-6 and inhibition of cell proliferation. These results demonstrate that pseudouridine-containing photolyase mRNA is a powerful tool to repair UVB-induced DNA lesions. The pseudouridine-modified mRNA approach has a strong potential to discern cellular effects of CPD in UV-related cell biological studies. The mRNA-based transient expression of proteins offers a number of opportunities for future application in medicine.
机译：UVB辐射会诱导有害的光化学反应，包括在DNA中形成环丁烷嘧啶二聚体（CPD）。未修复的CPD病变的积累会引起炎症，过早衰老和皮肤癌。光解酶是一种DNA修复酶，可以在称为光再活化的光依赖性过程中快速恢复DNA的完整性，但是在人类中却不存在。在这里，我们提出了一种新颖的基于mRNA的基因治疗方法，该方法指导培养的人类角质形成细胞中有袋，多孔三指，CPD-光解酶的合成。在体外转录过程中掺入了假尿苷，以使mRNA具有非免疫原性和高度可翻译性。用脂转染胺复合的mRNA转染的角质形成细胞在细胞核中表达光解酶至少2天。将光裂解酶mRNA转染的细胞暴露于UVB照射下，这些细胞中的CPD也显着降低，这也是光裂解酶活性所必需的。功能性光解酶还减少了其他UVB介导的作用，包括诱导IL-6和抑制细胞增殖。这些结果表明，含假尿苷的光解酶mRNA是修复UVB诱导的DNA损伤的有力工具。伪尿苷修饰的mRNA方法在紫外线相关的细胞生物学研究中具有很强的潜力来识别CPD的细胞作用。蛋白质基于mRNA的瞬时表达为医学上的未来应用提供了许多机会。

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