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

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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.