The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy
The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy
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DOI：
10.1038/s41588-019-0517-5
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发表时间：
2019-11-01
期刊：
影响因子：
30.8
通讯作者：
Supek, Fran
中科院分区：
文献类型：
--
作者：
Lindeboom, Rik G. H.;Vermeulen, Michiel;Supek, Fran
过早终止密码子（PTC）可导致截短蛋白质的产生或通过无义介导的mRNA衰变（NMD）降解信使RNA。这些结果中的哪一个发生都可以改变突变的效果，NMD的使用取决于一系列规则。在这里，通过将这些规则应用于全基因组以获得称为NMDetective的资源，我们探索了NMD对遗传疾病和治疗方法的影响。首先，人类遗传性疾病的不同之处在于NMD是否典型地增强或减弱PTC的影响。其次，未能触发NMD是CRISPR-Cas9基因编辑无效基因失活的原因。最后，NMD是癌症免疫疗法疗效的决定因素，只有逃避NMD的移码转录物才能预测反应。这些结果表明，将NMD的规则纳入临床决策的重要性。此外，他们认为抑制NMD可能有效地增强癌症免疫治疗。
Premature termination codons (PTCs) can result in the production of truncated proteins or the degradation of messenger RNAs by nonsense-mediated mRNA decay (NMD). Which of these outcomes occurs can alter the effect of a mutation, with the engagement of NMD being dependent on a series of rules. Here, by applying these rules genome-wide to obtain a resource called NMDetective, we explore the impact of NMD on genetic disease and approaches to therapy. First, human genetic diseases differ in whether NMD typically aggravates or alleviates the effects of PTCs. Second, failure to trigger NMD is a cause of ineffective gene inactivation by CRISPR-Cas9 gene editing. Finally, NMD is a determinant of the efficacy of cancer immunotherapy, with only frameshifted transcripts that escape NMD predicting a response. These results demonstrate the importance of incorporating the rules of NMD into clinical decision-making. Moreover, they suggest that inhibiting NMD may be effective in enhancing cancer immunotherapy.