Project title: Dissecting the Trypanosomal Interstrand Crosslink DNA REPAIRtoire
Summary: Interstrand crosslinks (ICLs) represent a particularly lethal form of DNA damage, a property exploited by some anticancer chemotherapies. To fix such lesions, cells have co-opted enzymes from different DNA repair pathways that together form an organism’s ‘ICL DNA REPAIRtoire’. Previous work has shown that the protozoan parasites responsible for trypanosomiasis and leishmaniasis are extremely sensitive to ICLs. This has led to the suggestion that compounds which promote this type of damage may have potential in treating these infections. Using a combination of biochemical, cell biology and functional genomic approaches, we plan to unravel how Trypanosoma brucei, the organism responsible for human and animal African trypanosomiasis, repairs ICLs and investigate the interaction and interplay of the components that constitute this particular pathogen’s ‘ICL DNA REPAIRtoire’. This will facilitate comparative studies against the ICL repair systems from other organisms, with any differences potentially exploitable in developing new drugs targeting African trypanosomiasis. It is envisaged that the identification and design of inhibitors that reduce the activity of key components of the trypanosome ‘ICL DNA REPAIRtoire’, without significantly affecting the host, would increase the trypanocidal effect of ICL-inducing agents, such as those we have previously identified.