Laboratory of Receptor Biology and Gene Expression, National Cancer Insitute, National Institutes of Health, Bethesda, Maryland 20892, USA.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes Dev. 2019 May 1;33(9-10):482-497. doi: 10.1101/gad.319590.118. Epub 2019 Mar 6.
Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.
剪接体成分编码基因的体细胞突变在人类肿瘤中经常发生，包括骨髓增生异常和白血病，在实体瘤中则较少发生。受影响的因素之一 U2AF1 参与剪接位点选择，最常见的变化 S34F 改变了保守的核酸结合域，识别 3' 剪接位点，并对许多 mRNA 的可变剪接产生影响。然而，这种突变在肿瘤发生中的作用仍然未知。在这里，我们揭示了 U2AF1 的一种非典型功能，表明它可以直接在细胞质中结合成熟的 mRNA，并负调控 mRNA 翻译。这种剪接独立的 U2AF1 作用被 S34F 突变所改变，多核糖体分析表明该突变影响了数百种 mRNA 的翻译。一个功能后果是增加了分泌趋化因子白细胞介素 8 的合成，这有助于在小鼠和人类中转移、炎症和癌症进展。
