DDX23 5' UTR 调控元件的结构性表征及其通过LNA-修改的反意义寡核酸来向的向
Polina Kamzeeva1, Nikita Shepelev1,2, Veronika Zabbarova2
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, The Russian Academy of Sciences, 117437 Moscow, Russia.
International journal of molecular sciences
|November 27, 2025
概括
研究人员探索了DDX23mRNA中的RNA结构,发现针头,而不是G-四重复合体,调节翻译. 针对这种针头的反感性寡核酸有效抑制了翻译,提供了新的抗癌治疗策略.
科学领域:
- 分子生物学分子生物学
- RNA结构和功能 RNA结构和功能
- 抗癌治疗药物 抗癌治疗药物
背景情况:
- mRNA翻译对于基因表达至关重要,5' UTRs调节核糖体招募.
- 在5' UTR中稳定的结构图案可以调节翻译效率.
- DDX23 mRNA编码了一种与抗癌疗法相关的蛋白质,使其调节成为一个关键目标.
研究的目的:
- 在DDX23mRNA的5' UTR中研究稳定的结构动机.
- 确定这些结构的调节作用,特别是RNA G-四复合体 (rG4s).
- 为治疗应用设计和测试针对这些动机的反意义寡核酸 (ASO).
主要方法:
- 生物信息学预测和转录基因验证.
- 结构分析使用光线测定,CD,UV和NMR光谱学.
- 记者用G4稳定器和ASO准进行分析.
- 用锁定核酸 (LNA) 修改的ASO的设计和测试.
主要成果:
- 在DDX23mRNA中,大多数预测的rG4形成序列不会形成稳定的rG4s.
- 在rG4和针头形状之间存在一个平衡的序列.
- 确定了具有调节功能的稳定发针结构.
- 顶端-近端ASO向抑制了DDX23翻译高达80%.
- 针对上游开放阅读框架 (uORF) 的目标是无效的.
结论:
- rG4s在DDX23 mRNA翻译中发挥着有限的调节作用.
- 一个稳定的发针结构是DDX23转化的一个关键调节器.
- ASO的设计原则包括避免uORF屏蔽区域,并优化ASO-RNA双重稳定性.
- 这项研究为开发以ASO为基础的针对mRNA翻译的抗癌疗法提供了框架.
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