由DUS3L进行的补偿性tRNA修改使食道癌症中对METTL1损失产生抗性
Helena Santos-Rosa1,2,3, Jonathan L Price1,2,3, Georgia Tsagkogeorga4,5,6
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
癌细胞依赖tRNA N7-甲基瓜诺辛 (m7G46) 进行增殖. 一些癌症通过增加二氨基基化 (D47),一种可用于治疗的途径,抵抗METTL1损失.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 生物化学 生化学
背景情况:
- 通过METTL1/WDR4修改tRNAN7-甲基瓜诺辛 (m7G46) 对tRNA稳定性和细胞增殖至关重要.
- 由于在许多细胞系中对其枯竭的敏感性,METTL1是癌症中潜在的治疗标.
- 癌症细胞系的一小部分表现出对METTL1损失的抵抗力,需要对潜在机制进行研究.
研究的目的:
- 用食道腺癌细胞系作为模型,阐明癌症中METTL1耐药性的机制.
- 确定在没有m7G46.6的情况下维持tRNA稳态的补偿途径.
- 探索针对这些补偿机制的治疗潜力.
主要方法:
- 研究了METTL1抗性和敏感细胞系,重点研究食道腺癌OE33.3.
- 分析了tRNA修改,特别是m7G46和在位置47 (D47) 的二氨基基化,使用DUS-L酶的耗尽.
- 评估了联合m7G46和D47损失对tRNA结构,细胞健康和基因表达的影响.
主要成果:
- 耐METTL1的OE33细胞通过调节D47修饰以应对m7G46缺陷来维持tRNA平衡.
- 催化D47的DUS-L酶的耗尽使OE33细胞对METTL1损失敏感.
- 失去m7G46和D47都会破坏tRNA结构的稳定,损害细胞健康,并显示METTL1-敏感细胞由于低DUS3L水平而缺乏这种补偿途径.
结论:
- 一个DUS-L介导的缓冲机制在METTL1-耐药癌症中维持tRNA稳态.
- DUS3L的丰度可以作为预测METTL1敏感性的生物标志物.
- 结合DUS-L和METTL1的向提供了一个潜在的治疗策略,以克服OE33.3等癌症的耐药性.
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