Translesion synthesis and microhomology-mediated end-joining repair in trypanosomatids

Trypanosomatid parasites and the diseases they cause affect more than 30 million people annually worldwide. To develop treatments for these diseases, it is critical to understand how trypanosomatid biology protects the parasite, so that these mechanisms may be exploited as drug targets. An important aspect of trypanosomatid survival is protection from oxidative damage inflicted by the host. Reactive oxygen species produced by the host can damage nuclear DNA and kinetoplast, the mitochondrion DNA. DNA damage must be repaired or bypassed for the trypanosomatid to continue to replicate its genome. Trypanosomatids also possess specialized redox pathways that neutralize reactive oxygen species (ROS) from host-derived attacks and endogenous mitochondrion metabolism. This Review Article focuses on how trypanosomatids employ microhomology-mediated end-joining to repair DNA double-strand breaks and translesion DNA synthesis to bypass oxidatively damaged bases in nuclear and kinetoplast DNA. While the deleterious effects of ROS must be managed to protect the parasite's genome, the redox status generated by oxidative assault is crucial for intracellular signaling, DNA synthesis, and kinetoplast homeostasis. This Review will also comment on the effectiveness of current treatments for trypanosomatid-caused diseases and the role of oxidative damage in trypanosomatid diversity.