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

复制应激反应的共同和不同特征如何塑造 TriTryp 寄生虫的生物学？

• 批准号: BB/N016165/1
• 负责人: Richard McCulloch
• 金额: $ 47.77万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN016165%2F1
• 关键词: How; do; common; diverged; features

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.

任何生物体的生长和繁殖都依赖于其基因组的忠实传递--基因物质为生命提供了蓝图。将基因组传递给后代需要复制遗传物质，然后分离。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，进一步的细胞机制既认识到，然后解决，允许复制过程的重新启动。复制的一个明显障碍是允许基因组中基因表达的细胞机制，并且已知基因表达和复制之间的冲突可能导致基因组变化。我们对一组称为动质体的寄生虫中的这些冲突感兴趣，它们一直是广泛研究的主题，至少部分是因为它们显示出相对于其他真核细胞而言非常规的生物学方面，并且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。先前的工作表明，基因表达尽管是任何细胞中最核心的过程之一，但在所有动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，同样的中央细胞反应，似乎不同的动质体寄生虫，它已被研究。这些发现向我们提出了两件我们希望检验的事情。首先，我们假设所有动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，需要强大的，也许是新颖的手段来解决这种类型的障碍，以完成基因组复制。其次，我们假设，在三种动质体中，处理这些碰撞的方法略有不同，导致它们的基因组出现不同形式的变异，从而导致它们与人类和其他哺乳动物之间的相互作用非常不同。通过测试这些假设，我们相信我们将揭示动质体和其他真核生物在基因组复制过程中使用的策略之间的差异或相似之处，这也可能揭示靶向寄生虫并减轻它们引起的疾病的途径。

项目成果

Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigens

• DOI: 10.1016/j.celrep.2019.12.049
• 发表时间: 2020-01-21
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Black, Jennifer Ann;Crouch, Kathryn;McCulloch, Richard
• 通讯作者: McCulloch, Richard

Additional file 3 of Replication origin location might contribute to genetic variability in Trypanosoma cruzi

复制起点位置的附加文件 3 可能导致克氏锥虫的遗传变异

• DOI: 10.6084/m9.figshare.12544151
• 发表时间: 2020
• 作者: Araujo C

Additional file 7 of Replication origin location might contribute to genetic variability in Trypanosoma cruzi

复制起点位置的附加文件 7 可能导致克氏锥虫的遗传变异

• DOI: 10.6084/m9.figshare.12544178
• 发表时间: 2020
• 作者: Araujo C

Chromosomal copy number variation analysis by next generation sequencing confirms ploidy stability in Trypanosoma brucei subspecies.

• DOI: 10.1099/mgen.0.000223
• 发表时间: 2018-10
• 期刊: Microbial genomics
• 影响因子: 3.9
• 作者: Almeida LV;Coqueiro-Dos-Santos A;Rodriguez-Luiz GF;McCulloch R;Bartholomeu DC;Reis-Cunha JL
• 通讯作者: Reis-Cunha JL

Additional file 2 of Replication origin location might contribute to genetic variability in Trypanosoma cruzi

复制起点位置的附加文件 2 可能导致克氏锥虫的遗传变异

• DOI: 10.6084/m9.figshare.12544145
• 发表时间: 2020
• 作者: Araujo C