美国约翰斯·霍普金斯大学Jiou Wang团队报道了解旋酶解六核苷酸可以重复RNA G-四链体并促进重复相关的非AUG翻译。相关研究成果于2021年4月15日发表在国际顶尖学术期刊《美国化学会杂志》。

C9orf72基因中六核苷酸重复序列GGGGCC（G4C2）的扩增是肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）最常见的病因。G4C2扩增导致重复相关的非AUG（RAN）翻译和毒性二肽重复（DPR）蛋白的产生，但RAN翻译的机制仍然是个谜。

该文中，研究人员发现RNA解旋酶DHX36是C9ORF72RAN翻译的一个强大的正调控因子。DHX36对G4C2重复序列RNA有很高的亲和力，优先结合重复序列RNA的G-四链构象，并有效地解封G4C2 G-四链结构。天然DHX36与G4C2重复RNA相互作用，对细胞中有效的RAN翻译至关重要。

在诱导的多能干细胞和来自C9orf72连锁ALS患者的分化运动神经元中，减少DHX36可以显著降低内源性DPR蛋白水平。DHX36在C9orf72连锁ALS患者的组织中也异常上调。以上结果表明，DHX36通过解析重复RNA G-四联体结构并促进C9orf72-RAN翻译可能是治疗干预的潜在目标。

附：英文原文

Title: A Helicase Unwinds Hexanucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation

Author: Honghe Liu, Yu-Ning Lu, Tapas Paul, Goran Periz, Michael T. Banco, Adrian R. Ferré-D’Amaré, Jeffrey D. Rothstein, Lindsey R. Hayes, Sua Myong, Jiou Wang

Issue&Volume: April 15, 2021

Abstract: The expansion of a hexanucleotide repeat GGGGCC (G4C2) in the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 expansion leads to repeat-associated non-AUG (RAN) translation and the production of toxic dipeptide repeat (DPR) proteins, but the mechanisms of RAN translation remain enigmatic. Here, we report that the RNA helicase DHX36 is a robust positive regulator of C9orf72 RAN translation. DHX36 has a high affinity for the G4C2 repeat RNA, preferentially binds to the repeat RNA’s G-quadruplex conformation, and efficiently unwinds the G4C2 G-quadruplex structures. Native DHX36 interacts with the G4C2 repeat RNA and is essential for effective RAN translation in the cell. In induced pluripotent stem cells and differentiated motor neurons derived from C9orf72-linked ALS patients, reducing DHX36 significantly decreased the levels of endogenous DPR proteins. DHX36 is also aberrantly upregulated in tissues of C9orf72-linked ALS patients. These results indicate that DHX36 facilitates C9orf72 RAN translation by resolving repeat RNA G-quadruplex structures and may be a potential target for therapeutic intervention.

DOI: 10.1021/jacs.1c00131

Source: https://pubs.acs.org/doi/10.1021/jacs.1c00131