A Helicase Unwinds Hexanucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation.
A Helicase Unwinds Hexanucleotide Repeat RNA G-Quadruplexes and Facilitates Repeat-Associated Non-AUG Translation.
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解旋酶解己核苷酸重复RNA g -四联体并促进重复相关的非aug翻译。
DOI：
10.1021/jacs.1c00131
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发表时间：
2021-05-19
影响因子：
15
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Liu H;Lu YN;Paul T;Periz G;Banco MT;Ferré-D'Amaré AR;Rothstein JD;Hayes LR;Myong S;Wang J
C9 orf 72基因中六核苷酸重复GGGGCC（G4 C2）的扩增是肌萎缩侧索硬化（ALS）和额颞叶痴呆（FTD）的最常见原因。G4 C2扩增导致重复相关的非AUG（RAN）翻译和有毒二肽重复（DPR）蛋白的产生，但RAN翻译的机制仍然是谜。在这里，我们报告说，RNA解旋酶DHX 36是一个强大的C9 orf 72 RAN翻译的正调控。DHX 36对G4 C2重复RNA具有高亲和力，优先结合重复RNA的G-四链体构象，并有效解绕G4 C2 G-四链体结构。天然DHX 36与G4 C2重复RNA相互作用，对于细胞中有效的RAN翻译至关重要。在来自C9 orf 72连锁ALS患者的诱导多能干细胞和分化的运动神经元中，减少DHX 36显著降低了内源性DPR蛋白的水平。DHX 36在C9 orf 72连锁的ALS患者的组织中也异常上调。这些结果表明DHX 36通过解析重复RNA G-四链体结构促进C9 orf 72 RAN翻译，并且可能是治疗干预的潜在靶标。
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.
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DOI：
10.1073/pnas.1422605112
发表时间：
2015-08-04
影响因子：
11.1
作者：
Heddi, Brahim;Cheong, Vee Vee;Anh Tuan Phan
通讯作者：
Anh Tuan Phan
影响因子：
64.8
作者：
Chen MC;Tippana R;Demeshkina NA;Murat P;Balasubramanian S;Myong S;Ferré-D'Amaré AR
通讯作者：
Ferré-D'Amaré AR
影响因子：
8.8
作者：
Fay MM;Anderson PJ;Ivanov P
通讯作者：
Ivanov P
影响因子：
2.9
作者：
Dodd, David W.;Tomchick, Diana R.;Gagnon, Keith T.
通讯作者：
Gagnon, Keith T.
G-四链体折叠和稳定性中的金属阳离子。
影响因子：
5.5
作者：
Bhattacharyya D;Mirihana Arachchilage G;Basu S
通讯作者：
Basu S