Gilbert Agathe, Saveanu Cosmin
Institut Pasteur, Sorbonne Université, CNRS UMR-3525, Paris, F-75015, France.
Bioessays. 2022 May;44(5):e2100296. doi: 10.1002/bies.202100296. Epub 2022 Mar 10.
Degradation of eukaryotic RNAs that contain premature termination codons (PTC) during nonsense-mediated mRNA decay (NMD) is initiated by RNA decapping or endonucleolytic cleavage driven by conserved factors. Models for NMD mechanisms, including recognition of PTCs or the timing and role of protein phosphorylation for RNA degradation are challenged by new results. For example, the depletion of the SMG5/7 heterodimer, thought to activate RNA degradation by decapping, leads to a phenotype showing a defect of endonucleolytic activity of NMD complexes. This phenotype is not correlated to a decreased binding of the endonuclease SMG6 with the core NMD factor UPF1, suggesting that it is the result of an imbalance between active (e.g., in polysomes) and inactive (e.g., in RNA-protein condensates) states of NMD complexes. Such imbalance between multiple complexes is not restricted to NMD and should be taken into account when establishing causal links between gene function perturbation and observed phenotypes.
在无义介导的mRNA衰变(NMD)过程中,真核生物中含有提前终止密码子(PTC)的RNA降解是由保守因子驱动的RNA去帽或核酸内切酶切割引发的。包括PTC识别或RNA降解的蛋白质磷酸化的时间和作用在内的NMD机制模型受到了新结果的挑战。例如,被认为通过去帽激活RNA降解的SMG5/7异二聚体的缺失,导致了一种表型,显示出NMD复合物的核酸内切酶活性缺陷。这种表型与核酸内切酶SMG6与核心NMD因子UPF1结合减少无关,这表明它是NMD复合物的活性状态(如在多核糖体中)和非活性状态(如在RNA-蛋白质凝聚物中)之间失衡的结果。多个复合物之间的这种失衡并不局限于NMD,在建立基因功能扰动与观察到的表型之间的因果联系时应予以考虑。