Fujino Yuzo, Mori Kohji, Nagai Yoshitaka
Department of Neurology, Faculty of Medicine, Kindai University 377-2 Ohnohigashi, Osaka-sayama, Osaka 589-8511, Japan.
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Kyoto 602-8566, Japan.
J Biochem. 2023 Mar 31;173(4):273-281. doi: 10.1093/jb/mvad012.
Expanded short tandem repeats cause more than 50 monogenic diseases, which are mostly neuromuscular diseases. In the non-coding repeat expansion diseases, in which the expanded repeat sequence is located outside of the coding region, the toxicity of the transcribed repeat-containing RNAs had been the focus of research. However, recent studies have revealed that repeat RNAs can be translated into repeat polypeptides, despite the lack of an AUG initiation codon, by non-canonical repeat-associated non-AUG translation (RAN translation). RAN translated repeat polypeptides have actually been confirmed in patients' tissues. Moreover, various cellular and animal disease models have demonstrated the toxicity of these peptides, suggesting the pathogenic roles of RAN translation in the repeat expansion diseases. In this review, we will outline RAN translation, from the viewpoint of its molecular mechanisms to its potential as a therapeutic target for the repeat expansion diseases.
扩展短串联重复序列导致50多种单基因疾病，其中大多数是神经肌肉疾病。在非编码重复序列扩增疾病中，扩增的重复序列位于编码区之外，含重复序列的转录RNA的毒性一直是研究的重点。然而，最近的研究表明，尽管缺乏AUG起始密码子，重复RNA仍可通过非经典的重复相关非AUG翻译（RAN翻译）翻译成重复多肽。RAN翻译的重复多肽已在患者组织中得到证实。此外，各种细胞和动物疾病模型已经证明了这些多肽的毒性，这表明RAN翻译在重复序列扩增疾病中具有致病作用。在这篇综述中，我们将从分子机制的角度概述RAN翻译及其作为重复序列扩增疾病治疗靶点的潜力。
