N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. Here, using human cells, we reveal that m6A sites in the coding sequence (CDS) trigger CDS-m6A decay (CMD), a pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3′ untranslated region, which to date have been considered the main effectors. Mechanistically, CMD depends on translation, whereby m6A deposition in the CDS triggers ribosome pausing and transcript destabilization. The subsequent decay involves the translocation of the CMD target transcripts to processing bodies (P-bodies) and recruitment of the m6A reader protein YT521-B homology domain family protein 2 (YTHDF2). Our findings highlight CMD as a previously unknown pathway, which is particularly important for controlling the expression of developmental regulators and retrogenes.

中文翻译：

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编码区的 m6A 位点触发翻译依赖性 mRNA 衰变


N6-甲基腺苷 （m6A） 是真核信使 RNA （mRNA） 中主要的内部 RNA 修饰，在 mRNA 稳定性中起着至关重要的作用。在这里，使用人类细胞，我们揭示了编码序列 （CDS） 中的 m6A 位点触发 CDS-m6A 衰变 （CMD），该途径与以前报道的 m6A 依赖性降解机制不同。重要的是，CDS m6A 位点比 3' 非翻译区的位点起作用更快、更有效，迄今为止，3' 非翻译区一直被认为是主要效应子。从机制上讲，CMD 依赖于翻译，因此 CDS 中的 m6A 沉积会触发核糖体暂停和转录本不稳定。随后的衰变涉及 CMD 靶转录物易位到加工体 （P 体） 和募集 m6A 读取蛋白 YT521-B 同源结构域家族蛋白 2 （YTHDF2）。我们的研究结果强调 CMD 是一种以前未知的途径，这对于控制发育调节因子和逆转录基因的表达尤为重要。