Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation
Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation
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DOI：
10.7554/elife.12765
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发表时间：
2016-05-26
期刊：
影响因子：
7.7
通讯作者：
McCulloch, Richard
中科院分区：
文献类型：
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作者：
Devlin, Rebecca;Marques, Catarina A.;McCulloch, Richard
布氏锥虫的生存依赖于其保护性变异体表面糖蛋白(VSG)外壳中的抗原变异所带来的开关。VSG的转换是通过频繁的同源重组发生的，这被认为需要位点特异性的启动。在这里，我们证明了RecQ解旋酶，RECQ2，作用于修复DNA断裂，包括在VSG表达的端粒位置。尽管如此，RECQ2缺失并不损害抗原变异，而是通过重组导致VSG开关增加，反对通过直接产生DNA双链断裂(DSB)来启动VSG开关的模型。事实上，我们发现DSB在VSG表达部位低效地直接重组。通过绘制基因组复制动态图，我们揭示了转录的VSG表达位点是唯一一个早期复制差异时序的端粒位点，这种差异时序只在哺乳动物感染的寄生虫中才能看到。VSG转录和复制时间之间的特定关联揭示了基于复制衍生DNA脆弱性的抗原变异模型。
Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication-derived DNA fragility.