Topoisomerase 3β is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction.
Topoisomerase 3β is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction.
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拓扑异构酶 3β 是 mRNA 的主要拓扑异构酶，与神经发育和精神功能障碍有关
DOI：
10.1093/nar/gkw1293
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发表时间：
2017-03-17
影响因子：
14.9
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Ahmad M;Shen W;Li W;Xue Y;Zou S;Xu D;Wang W
人类细胞在细胞核和细胞质中含有五种拓扑异构酶，但哪一种是mRNAs的主要拓扑异构酶尚不清楚。到目前为止，Top3β是唯一已知的具有β拓扑异构酶活性的拓扑异构酶，它结合mrna翻译机制并与rna结合蛋白fmrp相互作用促进突触形成；top3 mrp基因缺失与精神分裂症有关。在这里，我们发现Top3mRNA也是细胞中含量最丰富的β结合拓扑异构酶。Top3RNA，而不是其他拓扑异构酶，包含一个独特的β结合域；该结构域的缺失会减少与β结合的Top3β的数量，表明Top3RNA通过其RNA结合域特异性地靶向于mRNA。此外，缺乏其β结合域和催化残基的Top3突变体不能促进突触的形成，这表明Top3β既需要它的结合活性，也需要它的催化活性来促进神经发育。值得注意的是，精神分裂症和自闭症患者中携带点突变的Top3RNA蛋白与FMRP有关；而其中一个突变体也缺乏结合β、催化RNA拓扑异构酶反应和促进突触形成的能力。我们的数据表明，Top3RNA是β的主要拓扑异构酶，需要与RNA结合和催化活性来促进神经发育和预防精神障碍。
Human cells contain five topoisomerases in the nucleus and cytoplasm, but which one is the major topoisomerase for mRNAs is unclear. To date, Top3β is the only known topoisomerase that possesses RNA topoisomerase activity, binds mRNA translation machinery and interacts with an RNA-binding protein, FMRP, to promote synapse formation; and Top3β gene deletion has been linked to schizophrenia. Here, we show that Top3β is also the most abundant mRNA-binding topoisomerase in cells. Top3β, but not other topoisomerases, contains a distinctive RNA-binding domain; and deletion of this domain diminishes the amount of Top3β that associates with mRNAs, indicating that Top3β is specifically targeted to mRNAs by its RNA binding domain. Moreover, Top3β mutants lacking either its RNA-binding domain or catalytic residue fail to promote synapse formation, suggesting that Top3β requires both its mRNA-binding and catalytic activity to facilitate neurodevelopment. Notably, Top3β proteins bearing point mutations from schizophrenia and autism individuals are defective in association with FMRP; whereas one of the mutants is also deficient in binding mRNAs, catalyzing RNA topoisomerase reaction, and promoting synapse formation. Our data suggest that Top3β is the major topoisomerase for mRNAs, and requires both RNA binding and catalytic activity to promote neurodevelopment and prevent mental dysfunction.