Characterization of class II apurinic/apyrimidinic endonuclease activities in the human malaria parasite, Plasmodium falciparum

Haltiwanger, Brett M.; Karpinich, Natalie O.; Taraschi, Theodore F.

doi:10.1042/bj3450085

Cited by 12 publications

(2 citation statements)

References 38 publications

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“…Alternatively, during the base excision repair (BER) process, repair is initiated and damaged bases are excised by cleavage of the N-glycosidic bond and repair patches range from 1 to 6 nucleotides (9). To date, the only characterized repair pathway in the major malaria-causing parasite P. falciparum is the BER pathway (10,11).…”

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confidence: 99%

Defective DNA Repair as a Potential Mechanism for the Rapid Development of Drug Resistance in Plasmodium falciparum

et al. 2004

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The development and spread of highly drug-resistant parasites pose a central problem in the control of malaria. Understanding mechanisms that regulate genomic stability, such as DNA repair, in drug-resistant parasites and during drug treatment may help determine whether this rapid onset of resistance is due to an increase in the rate at which resistance-causing mutations are generated. This is the first report to demonstrate DNA repair activities from the malaria-causing parasite Plasmodium falciparum that are specific for ultraviolet light-induced DNA damage. The efficiency of DNA repair differs dramatically among P. falciparum strains with varying drug sensitivities. Most notable is the markedly reduced level of repair in the highly drug-resistant W2 isolate, which has been shown to develop resistance to novel drugs at an increased rate when compared to drug-sensitive strains. Additionally, the antimalarial drug chloroquine and other quinoline-like compounds interfered with the DNA synthesis step of the repair process, most likely a result of direct binding to repair substrates. We propose that altered DNA repair, either through defective repair mechanisms or drug-mediated inhibition, may contribute to the accelerated development of drug resistance in the parasite.

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confidence: 99%

Defective DNA Repair as a Potential Mechanism for the Rapid Development of Drug Resistance in Plasmodium falciparum

et al. 2004

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“…Base excision repair (BER) is the primary mechanism for repair of oxidative DNA lesions generated in organelle genomes due to reactive oxygen species (ROS) ( 27 ). Long-patch BER is reported in P. falciparum ( 28 , 29 ). Candidate P. falciparum apicoplast/mitochondrial DNA glycosylases/lyases that recognize and remove oxidised bases to generate apurinic/apyrimidinic (AP) sites have been identified but their organellar targeting is not yet confirmed ( 30 , 31 ).…”

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confidence: 99%

A Plasmodium apicoplast-targeted unique exonuclease/FEN exhibits interspecies functional differences attributable to an insertion that alters DNA-binding

Chatterjee,

Tiwari,

Gupta

et al. 2024

Nucleic Acids Research

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The human malaria parasite Plasmodium falciparum genome is among the most A + T rich, with low complexity regions (LCRs) inserted in coding sequences including those for proteins targeted to its essential relict plastid (apicoplast). Replication of the apicoplast genome (plDNA), mediated by the atypical multifunctional DNA polymerase PfPrex, would require additional enzymatic functions for lagging strand processing. We identified an apicoplast-targeted, [4Fe–4S]-containing, FEN/Exo (PfExo) with a long LCR insertion and detected its interaction with PfPrex. Distinct from other known exonucleases across organisms, PfExo recognized a wide substrate range; it hydrolyzed 5′-flaps, processed dsDNA as a 5′-3′ exonuclease, and was a bipolar nuclease on ssDNA and RNA–DNA hybrids. Comparison with the rodent P. berghei ortholog PbExo, which lacked the insertion and [4Fe–4S], revealed interspecies functional differences. The insertion-deleted PfExoΔins behaved like PbExo with a limited substrate repertoire because of compromised DNA binding. Introduction of the PfExo insertion into PbExo led to gain of activities that the latter initially lacked. Knockout of PbExo indicated essentiality of the enzyme for survival. Our results demonstrate the presence of a novel apicoplast exonuclease with a functional LCR that diversifies substrate recognition, and identify it as the candidate flap-endonuclease and RNaseH required for plDNA replication and maintenance.

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Uracil moieties in Plasmodium falciparum genomic DNA

et al. 2018

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Plasmodium falciparum parasites undergo multiple genome duplication events during their development. Within the intraerythrocytic stages, parasites encounter an oxidative environment and DNA synthesis necessarily proceeds under these circumstances. In addition to these conditions, the extreme AT bias of the P. falciparum genome poses further constraints for DNA synthesis. Taken together, these circumstances may allow appearance of damaged bases in the Plasmodium DNA . Here, we focus on uracil that may arise in DNA either via oxidative deamination or thymine‐replacing incorporation. We determine the level of uracil at the ring, trophozoite, and schizont intraerythrocytic stages and evaluate the base‐excision repair potential of P. falciparum to deal with uracil‐ DNA repair. We find approximately 7–10 uracil per million bases in the different parasite stages. This level is considerably higher than found in other wild‐type organisms from bacteria to mammalian species. Based on a systematic assessment of P. falciparum genome and transcriptome databases, we conclude that uracil‐ DNA repair relies on one single uracil‐ DNA glycosylase and proceeds through the long‐patch base‐excision repair route. Although potentially efficient, the repair route still leaves considerable level of uracils in parasite DNA , which may contribute to mutation rates in P. falciparum .

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Characterization of class II apurinic/apyrimidinic endonuclease activities in the human malaria parasite, Plasmodium falciparum

Cited by 12 publications

References 38 publications

Defective DNA Repair as a Potential Mechanism for the Rapid Development of Drug Resistance in Plasmodium falciparum

Defective DNA Repair as a Potential Mechanism for the Rapid Development of Drug Resistance in Plasmodium falciparum

A Plasmodium apicoplast-targeted unique exonuclease/FEN exhibits interspecies functional differences attributable to an insertion that alters DNA-binding

Uracil moieties in Plasmodium falciparum genomic DNA

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