小柯机器人

美国哈佛和麻省理工学院Todd R. Golub研究团队的最新研究揭示了非典型开放阅读框（ORF）编码癌细胞存活所必需的功能蛋白。这一研究成果于2021年1月29日发表在国际学术期刊《自然-生物技术》上。

研究人员运用实验方法检测了从非典型ORF数据集中选择的553个候选阅读框。其中，去除57种ORF会导致人类癌细胞系生存能力缺陷。利用异位表达，研究人员发现有257个具有蛋白质表达能力，而401个诱导了基因表达变化。成簇规律间隔短回文重复序列(CRISPR)切割和起始密码子诱变表明，其需要翻译而不是RNA介导来发挥生物学作用。

研究发现ORFs G029442（重命名为富含甘氨酸的细胞外蛋白1（GREP1））编码一种在乳腺癌中高度表达的分泌蛋白，在263株癌细胞系中的敲除数据表明其在乳腺癌衍生细胞系中具有优先必要性。表达GREP1的细胞外泌体高表达致癌细胞因子GDF15，并且补充GDF15可以减轻GREP1敲除造成的生长抑制作用。这些实验表明，非典型ORF可以表达具有生物活性的蛋白，其可作为潜在的治疗靶点。

据悉，尽管基因组分析预测了人类基因组中的许多非典型开放阅读框，但尚不清楚它们是否编码具有生物活性的蛋白质。

附：英文原文

Title: Noncanonical open reading frames encode functional proteins essential for cancer cell survival

Author: John R. Prensner, Oana M. Enache, Victor Luria, Karsten Krug, Karl R. Clauser, Joshua M. Dempster, Amir Karger, Li Wang, Karolina Stumbraite, Vickie M. Wang, Ginevra Botta, Nicholas J. Lyons, Amy Goodale, Zohra Kalani, Briana Fritchman, Adam Brown, Douglas Alan, Thomas Green, Xiaoping Yang, Jacob D. Jaffe, Jennifer A. Roth, Federica Piccioni, Marc W. Kirschner, Zhe Ji, David E. Root, Todd R. Golub

Issue&Volume: 2021-01-28

Abstract: Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We found that one of these ORFs, G029442—renamed glycine-rich extracellular protein-1 (GREP1)—encodes a secreted protein highly expressed in breast cancer, and its knockout in 263cancer cell lines showed preferential essentiality in breast cancer-derived lines. The secretome of GREP1-expressing cells has an increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth-inhibitory effect of GREP1 knockout. Our experiments suggest that noncanonical ORFs can express biologically active proteins that are potential therapeutic targets.

DOI: 10.1038/s41587-020-00806-2

Source: https://www.nature.com/articles/s41587-020-00806-2

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