Abstract
DNA replication must be closely controlled to ensure reliable maintenance of the genome in daughter cells. On the other hand, it is a process that can result in mutations. The balance between a careful process and an error-prone one results in higher or lower genetic variability. The aim of this project is to investigate the replication process in Trypanosoma cruzi, from the assembly of the pre-replication complex, through the activation of origins until eventual replicative stresses, in the context of its cell and life cycle. We intend to unravel the molecular mechanisms that allow (i) blocking replication in infectious forms; and (ii) the genetic variability of this organism, which is critical to the successful of the infection of the mammalian host. Reverse genetics, enzyme tagging, and characterization of post-translational protein modification techniques will allow the investigation of pre-replication and replication complex proteins. This approach will allow us to set up a robust scenario about the molecular mechanisms that T. cruzi uses to block DNA replication in infectious forms. Using Chip-seq and Gro-seq techniques, as well as mathematical modeling, we will investigate the replication dynamics. In this sense, we intend to evaluate the contribution of genome organization in this dynamic and to identify possible regions favorable to replicative stresses that may contribute to the genetic variability in T. cruzi. (AU)
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