Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan.
Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
Mol Cancer Res. 2023 Nov 1;21(11):1220-1233. doi: 10.1158/1541-7786.MCR-22-0877.
Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways.
EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.
越来越多的证据表明环状 RNA（circRNA）可作为蛋白质模板。然而，帽非依赖性翻译是如何被调控的仍很大程度上不明确。在这里，我们表明内含子的存在，因此剪接促进了帽非依赖性翻译。通过剪接后获得外显子连接复合物（EJC），促进了 circRNA 与核糖体之间的相互作用，从而促进了翻译。用剪接体抑制剂处理或突变剪接信号来阻止剪接，会阻碍 circRNA 的帽非依赖性翻译。此外，使用 Cas13 技术进行 EJC 连接重建了 EJC 依赖的 circRNA 翻译。最后，发现来自琥珀酸脱氢酶组装因子 2（circSDHAF2）的编码 circRNA 的水平在结直肠癌患者的肿瘤组织中升高，并在结直肠癌细胞和小鼠模型中显示出对肿瘤发生的关键作用。这些发现表明 EJC 介导的 circSDHAF2 翻译的帽非依赖性调控参与了致癌途径的调控。
EJC 介导的 circRNA 帽非依赖性翻译参与了结直肠癌的肿瘤发生。
