Arthur Laura, Pavlovic-Djuranovic Slavica, Smith-Koutmou Kristin, Green Rachel, Szczesny Pawel, Djuranovic Sergej
Washington University School of Medicine, Department of Cell Biology and Physiology. 600 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110.
Johns Hopkins School of Medicine, Department of Molecular Biology and Genetics. 725 N. Wolfe Street, Baltimore, MD 21205.
Sci Adv. 2015 Jul;1(6). doi: 10.1126/sciadv.1500154.
Regulation of gene expression involves a wide array of cellular mechanisms that control the abundance of the RNA or protein products of that gene. Here we describe a gene-regulatory mechanism that is based on poly(A) tracks that stall the translation apparatus. We show that creating longer or shorter runs of adenosine nucleotides, without changes in the amino acid sequence, alters the protein output and the stability of mRNA. Sometimes these changes result in the production of an alternative "frame-shifted" protein product. These observations are corroborated using reporter constructs and in the context of recombinant gene sequences. Approximately two percent of genes in the human genome may be subject to this uncharacterized, yet fundamental form of gene regulation. The potential pool of regulated genes encodes many proteins involved in nucleic acid binding. We hypothesize that the genes we identify are part of a large network whose expression is fine-tuned by poly(A)-tracks, and we provide a mechanism through which synonymous mutations may influence gene expression in pathological states.
基因表达调控涉及多种细胞机制，这些机制控制着该基因的RNA或蛋白质产物的丰度。在这里，我们描述了一种基于聚腺苷酸（poly(A)）序列的基因调控机制，该序列会使翻译装置停滞。我们表明，在不改变氨基酸序列的情况下，创建更长或更短的腺苷核苷酸序列会改变蛋白质产量和mRNA的稳定性。有时，这些变化会导致产生一种替代的“移码”蛋白质产物。使用报告基因构建体并在重组基因序列的背景下证实了这些观察结果。人类基因组中约2%的基因可能受到这种未被表征但基本的基因调控形式的影响。潜在的受调控基因库编码许多参与核酸结合的蛋白质。我们假设我们鉴定出的基因是一个大型网络的一部分，其表达通过聚腺苷酸序列进行微调，并且我们提供了一种机制，通过该机制同义突变可能在病理状态下影响基因表达。
