DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner.
DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner.
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DOI：
10.1007/s00401-021-02333-z
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发表时间：
2021-09
影响因子：
12.7
通讯作者：
Pandey UB
中科院分区：
文献类型：
--
作者：
Fortuna TR;Kour S;Anderson EN;Ward C;Rajasundaram D;Donnelly CJ;Hermann A;Wyne H;Shewmaker F;Pandey UB
在肉瘤(FUS)中融合的RNA结合蛋白的突变会导致肌萎缩侧索硬化症(ALS)，这是最常见的运动神经元病。细胞质聚集和缺陷的DNA修复机制在病因学上与突变的FUS相关的ALS有关。虽然FUS参与了RNA加工的许多方面，但人们对突变FUS的病理生理机制知之甚少。在这里，我们利用表达FUS的果蝇大脑中的RNA测序技术来识别与FUS介导的神经退化有关的显著改变的基因和途径。我们观察到DEAD-Box解旋酶17(DDX17)在果蝇和人类细胞系中的表达水平因突变的FUS而显著下调。突变体FUS将核DDX17招募到细胞质应激颗粒中，并通过FUS的Rgg1结构域与DDX17发生物理相互作用。DDX17的异位表达减少了突变的FUS在细胞质的错误定位和隔离到细胞质的应激颗粒中。我们发现DDX17是DNA损伤反应通路的一种新的调节子，它的上调修复了由突变的神经元FUS ALS引起的DNA损伤修复机制的缺陷。此外，我们发现DDX17是一种体内FUS介导的神经退行性变的新修饰物。我们的研究结果表明，突变的FUS下调了DDX17的表达，在体内，DDX17水平的恢复抑制了FUS介导的神经发病和毒性。
Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration. We observed the expression levels of DEAD-Box Helicase 17 (DDX17) to be significantly downregulated in response to mutant FUS in Drosophila and human cell lines. Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization and sequestration of mutant FUS into cytoplasmic stress granules. We identified DDX17 as a novel regulator of the DNA damage response pathway whose upregulation repairs defective DNA damage repair machinery caused by mutant neuronal FUS ALS. In addition, we show DDX17 is a novel modifier of FUS-mediated neurodegeneration in vivo. Our findings indicate DDX17 is downregulated in response to mutant FUS, and restoration of DDX17 levels suppresses FUS-mediated neuropathogenesis and toxicity in vivo.
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影响因子：
15.1
作者：
Baron DM;Kaushansky LJ;Ward CL;Sama RR;Chian RJ;Boggio KJ;Quaresma AJ;Nickerson JA;Bosco DA
通讯作者：
Bosco DA
影响因子：
16.6
作者：
Casci, Ian;Krishnamurthy, Karthik;Pandey, Udai Bhan
通讯作者：
Pandey, Udai Bhan
影响因子：
19
作者：
Boeynaems S;Alberti S;Fawzi NL;Mittag T;Polymenidou M;Rousseau F;Schymkowitz J;Shorter J;Wolozin B;Van Den Bosch L;Tompa P;Fuxreiter M
通讯作者：
Fuxreiter M
影响因子：
14.9
作者：
Abdelmohsen K;Tominaga K;Lee EK;Srikantan S;Kang MJ;Kim MM;Selimyan R;Martindale JL;Yang X;Carrier F;Zhan M;Becker KG;Gorospe M
通讯作者：
Gorospe M
影响因子：
5.7
作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW