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研究揭示无义介导mRNA降解所产生的影响
作者:小柯机器人 发布时间:2019/10/29 13:58:34

西班牙巴塞罗那科技学院Fran Supek和Ben Lehner等研究人员发现,无意介导的mRNA降解对遗传病、基因编辑和癌症免疫治疗的影响。该研究10月28日在线发表于《自然—遗传学》。

研究人员表示,过早的终止密码子(PTC)可能导致截短蛋白的产生或者通过无意义介导的mRNA降解(NMD)引起的信使RNA降解。这些结果中任一个的发生都可以改变突变的效果,NMD的参与取决于一系列规则。

通过应用这些规则在全基因组范围内获得的资源(称为NMDetective),研究人员探索了NMD对遗传疾病和治疗方法的影响。首先,人类遗传疾病的不同之处在于NMD要么通常会加剧要么会减轻PTC的影响。其次,无法触发NMD是CRISPR–Cas9基因编辑导致基因失活无效的原因。最后,NMD是癌症免疫疗法功效的决定因素,只有逃脱NMD的移码后转录本才能预测反应。

这些结果证明了将NMD规则纳入临床决策的重要性。此外,这些结果暗示抑制NMD可能有效增强癌症免疫疗法。

附:英文原文

Title: The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy

Author: Rik G. H. Lindeboom, Michiel Vermeulen, Ben Lehner, Fran Supek

Issue&Volume: 2019-10-28

Abstract: 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.

DOI: 10.1038/s41588-019-0517-5

Source: https://www.nature.com/articles/s41588-019-0517-5

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex