The ATR kinase of Trypanosoma brucei links DNA damage signalling and monoallelic control of surface antigen gene expression during antigenic variation
The ATR kinase of Trypanosoma brucei links DNA damage signalling and monoallelic control of surface antigen gene expression during antigenic variation
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DOI：
10.1101/435198
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发表时间：
2018-10
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影响因子：
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通讯作者：
J. Black;K. Crouch;L. Lemgruber;C. Lapsley;N. Dickens;J. Mottram;R. McCulloch
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文献类型：
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作者：
J. Black;K. Crouch;L. Lemgruber;C. Lapsley;N. Dickens;J. Mottram;R. McCulloch
为了逃避哺乳动物的免疫，布氏锥虫转换其表面表达的变异表面糖蛋白（VSG）。这个反应的关键是控制施加，以确保只有一个亚端粒多基因VSG表达位点被转录的时间。迄今为止，DNA修复活性仅涉及通过重组催化VSG转换，而不是转录控制。然而，如何VSG开关的信号引导适当的反应，或整合开关到寄生虫的生长，是未知的。在这里，我们表明，ATR，DNA损伤信号蛋白激酶的损失，是致命的，并导致核基因组病变增加。ATR缺失还导致细胞表面上混合VSG的表达，沉默表达位点的基因转录增加，以及RNA聚合酶I和VEX1（参与VSG转录的因子）的定位改变。因此，这项工作表明，VSG的表达控制是由核DNA损伤信号因子介导的。
To evade mammalian immunity, Trypanosoma brucei switches the variant surface glycoprotein (VSG) expressed on its surface. Key to this reaction are controls exerted to ensure only one of many subtelomeric multigene VSG expression sites are transcribed at a time. DNA repair activities have to date been implicated only in catalysis of VSG switching by recombination, not transcriptional control. However, how VSG switching is signalled to guide the appropriate reaction, or to integrate switching into parasite growth, is unknown. Here we show that loss of ATR, a DNA damage signalling protein kinase, is lethal and causes increased nuclear genome lesions. ATR depletion also causes expression of mixed VSGs on the cell surface, increased transcription of genes from silent expression sites, and altered localisation of RNA Polymerase I and VEX1, factors involved in VSG transcription. The work therefore reveals that VSG expression control is mediated by a nuclear DNA damage signalling factor.