DNA mismatch repair in Plasmodium falciparum: A potential mechanism for accelerated drug resistance
Plasmodium falciparum, the causative agent of the most lethal strain of human malaria, presents an enormous public health threat due to its ability to rapidly develop resistance to current antimalarial treatment. This accelerated resistance to multiple drugs, or ARMD phenotype, is widely documented, however, the molecular mechanisms that govern it are poorly understood. There is much precedence, both in human cancers and in bacterial systems, to implicate the DNA mismatch repair pathway in the parasitefs dramatic ability to quickly develop resistance to a multitude of antimalarials. DNA mismatch repair (MMR) is responsible for repairing mismatched bases that arise from replication, recombination, or DNA damaging agents and facilitates genomic fidelity by a thousand fold. Mutations in MMR genes have been linked to cancer, microsatellite instability, and chemotherapeutic drug resistance. Loss of mismatch repair is most commonly associated with drug resistance due to the rapid development of advantageous point mutations. In fact, there are several examples of P. falciparum drug resistance that can be traced directly back to one point mutation in a single gene. Among these examples are resistance to chloroquine and pyrimethamine, which can be traced to point mutations in the Pfcrt and Pfdhfr genes, respectively. While P. falciparum contains most key gene homologs required for mismatch repair, the actual repair efficiency of the parasite and how it correlates with drug resistance remain unexplored. We propose that drug resistant parasites have defective mismatch repair and that this defect has lent P. falciparum a mechanism for the development of advantageous point mutations. These parasites would then be selected for when placed under drug pressure. Using a versatile genetic assay, we established that drug sensitive HB3 parasites possess proficient, bi-directional mismatch repair. We also determined that the multiple drug resistant, ARMD parasites W2 and Dd2 have defective DNA mismatch repair activity. Dd2 was deficient in both 3' and 5' nick directed mismatch repair. The W2 strain demonstrated the absence of 3' nick directed MMR, but was proficient on 5' nicked substrates. This repair bias is attributable to the loss of a key mismatch repair protein, MLH1, which is known to be critical for 3' nick directed MMR. To our knowledge, these studies represent the first quantification of mismatch repair actitivy in P. falciparum and we now hope to begin to gain new insight on the mechanisms by which the malaria parasite quickly develops resistance to current antimalarial drugs.
Castellini, Meryl A, "DNA mismatch repair in Plasmodium falciparum: A potential mechanism for accelerated drug resistance" (2010). ETD Collection for Thomas Jefferson University. AAI3551456.