Polysome propensity and tunable thresholds in coding sequence length enable differential mRNA stability

The half-life of mRNAs, as well as their translation, increases proportionally to the optimal codons, indicating a tight coupling of codon-dependent differential translation and degradation. Little is known about the regulation of this coupling. We found that the coupling in yeast displays a dichotomous behavior regarding the mRNA coding sequence length. Below a critical length, codon optimality fails to affect the stability of mRNAs even though they can be efficiently translated into short peptides and proteins. Above this threshold length, codon optimality-dependent differential mRNA stability emerges in a switch-like fashion, which coincides with a similar increase in the polysome propensity of the mRNAs. This threshold length can be tuned by the untranslated regions (UTR). Some of these UTRs can destabilize mRNAs without reducing translation, which plays a role in controlling the amplitude of the oscillatory expression of cell-cycle genes. Our findings help understand the translation of short peptides from noncoding RNAs and the translation by localized monosomes in neurons.信使RNA（mRNA）的半衰期及其翻译效率随最优密码子的丰度呈正比例增长，表明密码子依赖的差异性翻译与降解过程存在紧密耦合。目前对于这种耦合关系的调控机制尚不清楚。我们的研究发现，酵母体内的这一耦合关系会随mRNA编码序列长度呈现二分性特征：当编码序列长度低于临界值时，即便mRNA能够被高效翻译为短肽与蛋白质，密码子最优性也无法影响其稳定性；当长度超过该临界阈值时，依赖密码子最优性的mRNA差异性稳定性会以开关式的方式出现，且这一现象与mRNA的多核糖体结合倾向性同步提升相契合。该临界长度可通过未翻译区域（untranslated region，UTR）进行调控。部分此类UTR可在不降低翻译效率的前提下降低mRNA的稳定性，这一机制对调控细胞周期基因振荡表达的振幅具有重要作用。我们的研究结果有助于理解非编码RNA翻译产生短肽的过程，以及神经元内局部单核糖体的翻译机制。