SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease.
SUMOylated Senataxin functions in genome stability, RNA degradation, and stress granule disassembly, and is linked with inherited ataxia and motor neuron disease.
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DOI：
10.1002/mgg3.1745
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发表时间：
2021-12
影响因子：
2
通讯作者：
La Spada AR
中科院分区：
文献类型：
--
作者：
Bennett CL;La Spada AR
Senataxin（SETX）是一种对神经元存活至关重要的DNA/RNA解旋酶。SETX突变是两种遗传性神经退行性疾病的基础：共济失调伴眼用不能2型（AOA 2）和肌萎缩侧索硬化4型（ALS 4）。本文综述SETX的关键细胞过程，我们假设，SETX需要SUMO翻译后修饰功能正常。SETX在细胞周期的S期定位于不同的病灶，这些病灶代表DNA聚合酶/RNA聚合酶II（RNAP）碰撞的位点，因为它们与DNA损伤标记物53 BP 1和H2 AX共定位。在这些位点，SETX将不完整的RNA转录物引导至核外泌体，通过与外泌体组分9（Exosc 9）（核外泌体的关键组分）的相互作用进行降解。这些过程需要SETX SUMO化。SETX最近也被定位在应激颗粒（SG）内，并发现调节SG解体，这是一个同样需要SUMO化的过程。SETX经历SUMO修饰以在循环细胞中的S期病灶处起作用以促进RNA降解。SETX可能在RNAP II双向自碰撞位点调节非分裂神经元中的类似过程。最后，SETX的SUMO化似乎是SG分解所需的。这种SETX功能可能对神经元存活至关重要，因为改变的SG动力学与ALS疾病的发病机制有关。此外，AOA 2点突变已显示阻断SETX SUMO化。这种突变诱导的共济失调表型与SETX无效突变的表型无法区分，强调了这种修饰的重要性。这篇迷你综述总结了SETX生物学最相关的方面，这些方面最近被发现与其SUMO翻译后修饰有关。Senataxin（SETX）是一种解旋酶，其功能是维持基因组稳定性，SETX类别特异性突变会导致严重的隐性共济失调（AOA 2）或显性运动神经元疾病（ALS 4）。RNA加工和结合蛋白如SETX仍然是神经系统疾病的主要焦点。然而，导致病理学的确切机制是难以捉摸的。
Senataxin (SETX) is a DNA/RNA helicase critical for neuron survival. SETX mutations underlie two inherited neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and Amyotrophic Lateral Sclerosis type 4 (ALS4). This review examines SETX key cellular processes and we hypothesize that SETX requires SUMO posttranslational modification to function properly. SETX is localized to distinct foci during S‐phase of the cell cycle, and these foci represent sites of DNA polymerase/RNA polymerase II (RNAP) collision, as they co‐localize with DNA damage markers 53BP1 and H2AX. At such sites, SETX directs incomplete RNA transcripts to the nuclear exosome for degradation via interaction with exosome component 9 (Exosc9), a key component of the nuclear exosome. These processes require SETX SUMOylation. SETX was also recently localized within stress granules (SGs), and found to regulate SG disassembly, a process that similarly requires SUMOylation. SETX undergoes SUMO modification to function at S‐phase foci in cycling cells to facilitate RNA degradation. SETX may regulate similar processes in non‐dividing neurons at sites of RNAP II bidirectional self‐collision. Finally, SUMOylation of SETX appears to be required for SG disassembly. This SETX function may be crucial for neuron survival, as altered SG dynamics are linked to ALS disease pathogenesis. In addition, AOA2 point mutations have been shown to block SETX SUMOylation. Such mutations induce an ataxia phenotype indistinguishable from those with SETX null mutation, underscoring the importance of this modification. This mini‐review summarizes the most pertinent aspects of SETX biology that have recently been found to coalesce around its SUMO posttranslational modification. Senataxin (SETX) is a helicase that functions to maintain genomic stability, and SETX class‐specific mutations cause either a severe recessive ataxia (AOA2) or a dominant motor neuron disease (ALS4). RNA processing and binding proteins such as SETX remain of major focus in neurologic disease. Yet, the precise mechanism leading to pathology is elusive.
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影响因子：
16
作者：
Marmor-Kollet H;Siany A;Kedersha N;Knafo N;Rivkin N;Danino YM;Moens TG;Olender T;Sheban D;Cohen N;Dadosh T;Addadi Y;Ravid R;Eitan C;Toth Cohen B;Hofmann S;Riggs CL;Advani VM;Higginbottom A;Cooper-Knock J;Hanna JH;Merbl Y;Van Den Bosch L;Anderson P;Ivanov P;Geiger T;Hornstein E
通讯作者：
Hornstein E
影响因子：
6.1
作者：
Chen, Ying-Zhang;Hashemi, Sayed H.;Bennett, Craig L.
通讯作者：
Bennett, Craig L.
影响因子：
14.5
作者：
Rabin, BA;Griffin, JW;Cornblath, DR
通讯作者：
Cornblath, DR
影响因子：
5.3
作者：
Rasmussen, TP;Culbertson, MR
通讯作者：
Culbertson, MR
影响因子：
4.5
作者：
Becherel OJ;Yeo AJ;Stellati A;Heng EY;Luff J;Suraweera AM;Woods R;Fleming J;Carrie D;McKinney K;Xu X;Deng C;Lavin MF
通讯作者：
Lavin MF