Popp Maximilian W, Maquat Lynne E
1] Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA [2] Center for RNA Biology, University of Rochester, Rochester, New York 14642, USA.
Nat Commun. 2015 Mar 26;6:6632. doi: 10.1038/ncomms7632.
Nonsense-mediated mRNA decay (NMD) limits the production of aberrant mRNAs containing a premature termination codon and also controls the levels of endogenous transcripts. Here we show that when human cells are treated with clinically used chemotherapeutic compounds, NMD activity declines partly as a result of the proteolytic production of a dominant-interfering form of the key NMD factor UPF1. Production of cleaved UPF1 functions to upregulate genes involved in the response to apoptotic stresses. The biological consequence is the promotion of cell death. Combined exposure of cells to a small-molecule inhibitor of NMD, NMDI-1, and the chemotherapeutic doxorubicin leads to enhanced cell death, while inhibiting UPF1 cleavage protects cells from doxorubicin challenge. We propose a model to explain why the expression levels of genes producing mRNAs of diverse structure that encode proteins of diverse function are under the purview of NMD.
无义介导的mRNA降解（NMD）限制了含有提前终止密码子的异常mRNA的产生，并且还控制内源性转录本的水平。在此我们表明，当用临床使用的化疗化合物处理人类细胞时，NMD活性部分下降是由于关键NMD因子UPF1的一种显性干扰形式的蛋白水解产生。切割后的UPF1的产生起到上调参与凋亡应激反应的基因的作用。生物学后果是促进细胞死亡。细胞联合暴露于NMD的小分子抑制剂NMDI-1和化疗药物阿霉素会导致细胞死亡增强，而抑制UPF1切割可保护细胞免受阿霉素的挑战。我们提出了一个模型来解释为什么产生具有不同结构的mRNA且编码不同功能蛋白质的基因的表达水平受NMD的调控。
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