近日，美国康奈尔大学教授Samie R. Jaffrey及其小组揭示了m⁶A改变核糖体动力学以启动mRNA降解。这一研究成果发表在2025年5月5日出版的国际学术期刊《细胞》上。

研究组发现m⁶A显著改变核糖体动力学，这些改变介导了m⁶A对mRNA的降解作用。研究人员发现m⁶A是核糖体失速的有效诱导剂，这些失速导致核糖体碰撞，形成与其他情况不同的独特构象。课题组研究人员发现核糖体的停滞程度与m⁶a介导的mRNA降解有关，而碰撞核糖体持续时间的增加与m⁶a介导的mRNA降解增强有关。核糖体在m⁶A处停滞和碰撞之后，YTHDF m⁶A读取器蛋白的募集促进mRNA降解。研究组展示了减少核糖体失速和碰撞的机制，如应激期间的翻译抑制，稳定m⁶A-mRNA并增加其丰度，从而实现应激反应。总的来说，他们的研究揭示了核糖体是m⁶A mRNA开始降解的初始m⁶A传感器。

研究人员表示，含有N⁶-甲基腺苷（m⁶A）的mRNA的降解对细胞生长、分化和应激反应至关重要。

附：英文原文

Title: m6A alters ribosome dynamics to initiate mRNA degradation

Author: Shino Murakami, Anthony O. Olarerin-George, Jianheng Fox Liu, Sara Zaccara, Ben Hawley, Samie R. Jaffrey

Issue&Volume: 2025-05-05

Abstract: Degradation of mRNA containing N6-methyladenosine (m6A) is essential for cell growth, differentiation, and stress responses. Here, we show that m6A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m6A on mRNA. We find that m6A is a potent inducer of ribosome stalling, and these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts. We find that the degree of ribosome stalling correlates with m6A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m6A-mediated mRNA degradation. Ribosome stalling and collision at m6A is followed by recruitment of YTHDF m6A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m6A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m6A sensor for beginning m6A-mRNA degradation.

DOI: 10.1016/j.cell.2025.04.020

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00455-6