PDF(Pubmed)
Abstract：
Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation.
摘要：
细胞衰老的特征是蛋白质合成减少，尽管基本过程大多不清楚。转移RNA（tRNA）的化学修饰经常影响tRNA活性，这对翻译至关重要。我们描述了tRNAN7-甲基鸟苷（m7G46）甲基化，由METTL1-WDR4催化，调节翻译并影响衰老表型。Mettl1/Wdr4和m7G随衰老而逐渐减弱。METL1的减少导致tRNA的减少，尤其是那些修改了m7G的人，通过快速tRNA降解（RTD）途径。减少导致核糖体在某些密码子处停滞，阻碍在Wnt信号传导和核糖体生物发生等途径中必需的mRNA的翻译。此外，慢性核糖体停滞刺激利波毒性和综合应激反应，诱导衰老相关的分泌表型。此外，恢复eEF1A蛋白通过降低RTD减轻METTL1缺乏引起的衰老表型。我们的发现表明，通过实现有效的mRNA翻译，tRNAm7G修饰对于预防过早衰老和衰老至关重要。
