How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites?

任何生物体的生长和繁殖都依赖于其基因组的忠实传递——基因组是提供生命蓝图的遗传物质。基因传递给后代需要基因物质被复制，然后被分离。复制过程称为复制。在复制过程中，指导这一过程的复杂机制遇到了许多障碍，这些障碍被进一步的细胞机制识别并解决，从而允许复制过程重新开始。复制的一个明显障碍是细胞的机制，它允许基因在基因组中表达，众所周知，基因表达和复制之间的冲突会导致基因组的变化。我们对一组被称为着丝质体的寄生虫中的这些冲突很感兴趣，它们已经成为广泛研究的主题，至少部分原因是它们表现出的许多生物学方面与其他真核细胞相比是非常规的，因为它们在世界范围内造成了明显的人类痛苦和经济困难。先前的研究表明，尽管基因表达是任何细胞中最核心的过程之一，但在所有着丝质体中都是非常规的。此外，我们最近的工作表明，基因组复制，一个同样重要的细胞反应，似乎在研究的着丝质体寄生虫之间有所不同。这些发现向我们提出了两件事，我们希望对此进行检验。首先，我们假设所有的着丝质体都有一个共同的问题，即基因表达和复制之间的冲突水平升高，因此需要强有力的、也许是新颖的手段来解决这类障碍，以完成基因组复制。其次，我们假设，在三种着丝质体中，处理这些碰撞的方法有细微的不同，导致它们的基因组有不同形式的变异，这导致它们与被感染的人类和其他哺乳动物表现出非常不同的相互作用。通过测试这些假设，我们相信我们将揭示着丝质体和其他真核生物在基因组复制过程中使用的策略的差异或相似之处，这也可能揭示针对寄生虫和减轻它们引起的疾病的途径。

The growth and propagation of any living organism is dependent on the faithful transmission of its genome - the genetic material that provides the blueprint for life. Transmission of the genome to offspring requires that the genetic material is copied and then segregated. The copying process is referred to as replication. During replication, the complex machinery that directs this process encounters many obstacles, which further cellular machinery both recognises and then resolves, allowing restart of the replication process. One pronounced obstacle to replication is the cell's machinery that allows expression of the genes in the genome, and it is known that clashes between gene expression and replication can result in genome changes. We are interested in these clashes in a set of parasites termed the Kinetoplastids, which have been the subject of extensive study, at least in part because they display numerous aspects of their biology that are unconventional relative to other eukaryotic cells and because they cause pronounced human suffering and economic hardship world-wide. Previous work has suggested that gene expression, despite being one of the most central processes in any cell, is unconventional in all kinetoplastids. In addition, our recent work has shown that genome replication, an equally central cellular reaction, appears to differ between the kinetoplastid parasites in which it has been studied. These findings suggest to us two things, which we wish to test. First, we hypothesise that all kinetoplastids share a common problem of elevated levels of clashes between gene expression and replication, necessitating robust and perhaps novels means to tackle this type of obstacle to allow the completion of genome copying. Second, we hypothesise that the means that are adopted to tackle these collisions are subtly different in the three kinetoplastids, resulting in different forms of variation in their genomes, which lead to the very different interactions that they display with the humans and other mammals that they infect. By testing these hypotheses, we believe that we will reveal differences or similarities between kinetoplastids and other eukaryotes in the strategies used during genome replication, which may also reveal pathways to target the parasites and alleviate the diseases they cause.