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The aim of our research is to understand the biology of malaria parasites and thereby coming up with smarter strategies to curb malaria. The focus of my talk will be the homologous recombination (HR) pathway and how this pathway can be blocked to arrest parasite growth. In Plasmodium Rad51 mediated HR mechanism and homology independent alternative end-joining mechanism have been identified. We have generated a parasite line defective in HR function and demonstrated that these parasites are unable to repair DSBs, suggesting that HR is the predominant DSB repair pathway in Plasmodium and HR activity cannot be compensated by other DSB repair mechanisms. Further, we have identified chemical inhibitor of HR pathway (B02) in Plasmodium. We found that the anti-parasitic activity of B02 synergies with two first-line malaria drugs Artemisinin (ART)and Chloroquine (CQ). We have worked out the detailed molecular mechanism of such synergism. Having these two important tools, the functional knockout and chemical inhibitor of HR pathway in hand, we have also investigated its role in maintenance and repair of mitochondria genome. The roles of HR in the diversification of variable antigens and the cross-talk between different epigenetic marks in the expression of the variable antigens were also investigated. The implications of our findings in controlling malaria will be discussed. |