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

Resumo

Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. (tritryps) present different in their life cycles as well as in their strategy for vertebrate infection. These differences in core biology are influenced by the ability of the parasites to maintain and alter their genome, leading to adaptive changes in gene expression. Gene expression is organized almost exclusively as polycistronic transcription, where every gene is expressed from one of a small number of a multigene units meaning that RNA Polymerase needs to traverse unusually long distances. The nature of transcription in each genome must predispose the parasites to pronounced replication stress due to collision between the replication and transcription machineries, leading to DNA replication fork stalling. In such stress conditions, the halted DNA fork is recognized by kinases ATM and ATR, which initiate a signaling cascade that mediates the appropriate response to the blockade. The nature of the replication stress signaling or the mechanisms of response are not the same in the tritryps and differences in genome architecture in the tritryps may be related to differing strategies used to resolve replication stress due to clashes with transcription. Specifically, it might be predicted that T. brucei activates dormant origins in conditions of stress, whereas T. cruzi and Leishmania resolve the stalled forks using recombination/amplification. We aim to determine if replication-transcription clashes are the main cause of the different genome architectures, and to reveal and compare the strategies used to resolve a stalled DNA replication forks in the parasites. (AU)