Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigens
Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigens
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DOI：
10.1016/j.celrep.2019.12.049
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发表时间：
2020-01-21
期刊：
影响因子：
8.8
通讯作者：
McCulloch, Richard
中科院分区：
文献类型：
--
作者：
Black, Jennifer Ann;Crouch, Kathryn;McCulloch, Richard
布氏锥虫逃避哺乳动物的免疫，通过使用重组来切换其表面表达的变体表面糖蛋白（VSG），同时确保只有一个亚端粒多基因VSG表达位点的时间被转录。DNA修复活性已经涉及通过重组而不是转录控制催化VSG转换。VSG转换如何被信号化以引导适当的反应或将转换整合到寄生虫生长中是未知的。在这里，我们表明，ATR的损失，DNA损伤信号蛋白激酶，是致命的，导致核基因组的不稳定性和增加VSG开关通过VSG局部损伤。此外，ATR损失导致沉默VSG表达位点的转录增加和细胞表面上混合VSG的表达，这些效应与RNA聚合酶I和VEX1的改变的定位相关。这项工作表明ATR通过DNA损伤信号传导和表面抗原表达控制在抗原变异中起作用。
Trypanosoma brucei evades mammalian immunity by using recombination to switch its surface-expressed variant surface glycoprotein (VSG), while ensuring that only one of many subtelomeric multigene VSG expression sites are transcribed at a time. DNA repair activities have been implicated in the catalysis of VSG switching by recombination, not transcriptional control. How VSG switching is signaled to guide the appropriate reaction or to integrate switching into parasite growth is unknown. Here, we show that the loss of ATR, a DNA damage-signaling protein kinase, is lethal, causing nuclear genome instability and increased VSG switching through VSG-localized damage. Furthermore, ATR loss leads to the increased transcription of silent VSG expression sites and expression of mixed VSGs on the cell surface, effects that are associated with the altered localization of RNA polymerase I and VEX1. This work shows that ATR acts in antigenic variation both through DNA damage signaling and surface antigen expression control.