Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA.
Department of Neurology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, USA.
RNA. 2022 Feb;28(2):123-138. doi: 10.1261/rna.078963.121. Epub 2021 Nov 30.
repeat expansion in the first intron of causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of () repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced () repeat-containing RNA is a substrate for DPR protein synthesis. () repeat-containing RNA translation is 5' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded () repeat-containing RNA in disease.
导致肌萎缩性侧索硬化症和额颞叶痴呆的第一个内含子中的重复扩展。重复包含的 RNA 被翻译成二肽重复（DPR）蛋白，其中一些是神经毒性的。使用动态核糖体分析，我们在（）重复上游的内含子中鉴定了三个翻译起始位点；这些位点的检测与重复的存在与否无关。在易位过程中，核糖体似乎在重复上停滞不前。在前一个外显子中的一个 AUG 起始一个 uORF，抑制下游翻译。多核糖体分离表明，未剪接的（）重复包含的 RNA 是 DPR 蛋白合成的底物。（）重复包含的 RNA 翻译是 5' 帽非依赖性的，但被起始因子 DAP5 抑制，这表明与 uORF 功能的相互作用。这些结果定义了疾病中扩展的（）重复包含的 RNA 的新型翻译机制。
