Peptidyl-tRNA hydrolysis rate influences the efficiency of nonsense-mediated mRNA decay.
Peptidyl-tRNA hydrolysis rate influences the efficiency of nonsense-mediated mRNA decay.
复制标题
肽基-tRNA 水解速率影响无义介导的 mRNA 降解的效率。
DOI：
10.1101/2024.01.10.575080
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Jagannathan,Sujatha
中科院分区：
文献类型：
--
作者：
Kolakada,Divya;Fu,Rui;Biziaev,Nikita;Shuvalov,Alexey;Lore,Mlana;Campbell,AmyE;Cortázar,MichaelA;Sajek,MarcinP;Hesselberth,JayR;Mukherjee,Neelanjan;Alkalaeva,Elena;Jagannathan,Sujatha
无意义介导的mRNA衰变（NMD）是一种质量控制机制，通过降解带有过早终止密码子（ptc）的转录本来防止有害截断蛋白的积累。NMD的活性在许多情况下有所不同，这种变化在正常发育和疾病期间都具有重要的后果。然而，影响这种变异性的因素仍然知之甚少。在这里，我们研究了PTC的直接序列上下文与NMD活性之间的关系。我们发现在普通无义变异中，甘氨酸（Gly）密码子在PTC之前富集，而在正常终止密码子（NTC）之前，甘氨酸（Gly）密码子耗尽。此外，Gly-PTC富集在耐受功能丧失变异的基因中最为明显，这表明Gly-PTC环境具有生物学影响。与这一观点相一致，Gly-PTC背景比丙氨酸- ptc背景具有更高的NMD活性。我们使用大规模平行报告基因实验来全面评估PTC序列上下文对NMD活性的影响，结果表明翻译终止时肽基trna水解率是区分NMD活性高低的最重要特征。我们在真核系统中进行了生化分析，结果表明Gly-TC上下文与其他密码子相比具有最慢的终止率。基于这些发现，我们提出NMD活性是由肽基trna水解速率和翻译终止动力学提供的“机会之窗”调节的。Gly-PTC背景可能与NMD共同进化，以确保从非必需基因中剔除潜在毒性的截断蛋白。
Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that prevents the accumulation of harmful truncated proteins by degrading transcripts with premature termination codons (PTCs). NMD activity varies across many contexts, with the variation having critical consequences during both normal development and disease. However, the factors that influence this variability remain poorly understood. Here, we investigate the relationship between the immediate sequence context of a PTC and NMD activity. We find an enrichment of glycine (Gly) codons preceding a PTC in common nonsense variants in contrast with a depletion of Gly codons preceding a normal termination codon (NTC). Furthermore, Gly-PTC enrichment is most pronounced in genes that tolerate loss-of-function variants, suggesting a biological impact for Gly-PTC contexts. Consistent with this idea, Gly-PTC contexts have higher NMD activity compared to an alanine-PTC context. We used a massively parallel reporter assay to comprehensively assess the effect of PTC sequence context on NMD activity, which revealed that peptidyl-tRNA hydrolysis rate during translation termination was the most important feature in discriminating high and low NMD activity. We show with biochemical assays in a eukaryotic system that Gly-TC contexts have the slowest termination rate compared to other codons. Based on these findings, we propose that NMD activity is modulated by the “window of opportunity” offered by peptidyl-tRNA hydrolysis rate and thus, translation termination kinetics. Gly-PTC contexts may have coevolved with NMD to ensure robust elimination of potentially toxic truncated proteins from non-essential genes.
影响因子：
14.9
作者：
Grosjean H;Westhof E
通讯作者：
Westhof E
影响因子：
4.5
作者：
Frolova, LY;Tsivkovskii, RY;Kisselev, LL
通讯作者：
Kisselev, LL
影响因子：
5.6
作者：
BONETTI, B;FU, LW;BEDWELL, DM
通讯作者：
BEDWELL, DM