DNA damage regulation and its role in drug-related phenotypes in the malaria parasites

Gupta, Devendra; Patra, Alok Tanala; Zhu, Lei; Gupta, Archana Patkar; Bozdech, Zbynek

doi:10.1038/srep23603

Cited by 68 publications

(91 citation statements)

References 89 publications

(139 reference statements)

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“…Of the ~ 30 P. falciparum DNA repair genes reported to be upregulated upon MMS treatment , three are putative organellar DNA repair components. These include the DNA glycosylase Ogg1 homolog, a 5′–3′ exonuclease, and a 3′–5′ exonuclease.…”

Section: Discussionmentioning

confidence: 99%

“…The Plasmodium falciparum apicoplast genome is a 35‐kb circular DNA molecule and the mitochondrial genome is a linear, tandemly repeated 6‐kb DNA element . Repair of these genomes would be necessary for the maintenance of the integrity of the coding sequence during replication or upon exposure to endogenous or exogenous genotoxins; alteration of DNA repair proteins also has implications in the generation of resistance to frontline antimalarials .…”

Section: Introductionmentioning

confidence: 99%

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Plasmodium falciparum Apn1 homolog is a mitochondrial base excision repair protein with restricted enzymatic functions

et al. 2019

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The malaria parasite carries two organelles, the apicoplast and mitochondrion, whose DNA genomes must be maintained for optimal function and parasite survival under genotoxic stress. DNA repair mechanism(s) operative within these organelles were explored by mining the Plasmodium falciparum nuclear genome for sequences encoding proteins of major DNA repair pathways with predicted targeting to either organelle. Of the panel of enzymes identified for base excision repair (BER), we characterized the apurinic/apyrimidinic (AP) endonuclease PfApn1—an EndoIV whose homolog is not known in humans. PfApn1 targeted to the mitochondrion and functioned as an AP endonuclease requiring both Zn2+ and Mn2+ ions for maximal activity. Mutation of the critical third metal‐binding site residue H542 resulted in the loss of Mn2+ (but not Zn2+) binding indicating that Mn2+ bound PfApn1 at this site; this was further supported by molecular dynamic simulation. CD spectra analysis further showed requirement of both metal ions for the attainment of PfApn1 β‐strand‐rich optimal conformation. PfApn1 also functioned as a 3′‐phosphatase that would enable removal of 3′‐blocks for DNA polymerase activity during BER. Interestingly, unlike Escherichia coli and yeast EndoIV homologs, PfApn1 lacked 3′–5′ exonuclease activity and also did not cleave damaged bases by nucleotide incision repair (NIR). Uncoupling of endonuclease/phosphatase and exonuclease/NIR in PfApn1 suggests that amino acid residues distinct from those critical for endonuclease function are required for exonuclease activity and NIR. Characterization of a critical mitochondrion‐targeted AP endonuclease provides evidence for a functional BER pathway in the parasite organelle.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum Apn1 homolog is a mitochondrial base excision repair protein with restricted enzymatic functions

et al. 2019

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“…All markers associated with mismatch repair and double-strand break repair 34 (e.g. repair proteins RAD54 and RAD51 35 ) show decreased abundance in the cell cycle-arrested transcriptome (Supplementary File S2), in contrast to treatment with DNA-damaging agents such as methyl methanesulphonate, cisplatin and etoposide, which upregulate multiple DNA repair pathways 36 .…”

Section: Molecular Characteristics Of a Cell Cycle Arrest At The G 1 mentioning

confidence: 99%

“…(e.g. repair proteins RAD54 and RAD5135 ) show decreased abundance in the cell cycle-arrested transcriptome (Supplementary File S2), in contrast to treatment with DNA-damaging agents such as methyl methanesulphonate, cisplatin and etoposide, which upregulate multiple DNA repair pathways36 . Transcriptomes of drug-treated asexual parasites33 and parasites undergoing amino acid starvation16 (turquoise circle, Starve) were separated with a support vector machine (SVM) classifier and subsequently clustered in order to establish relatedness of chemical perturbations to cell cycle-arrested parasites (2 mM DFMO-treated, 24 h, orange circle).…”

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confidence: 99%

Inducing controlled cell cycle arrest and re-entry during asexual proliferation ofPlasmodium falciparummalaria parasites

Biljon

Niemand

Wyk

et al. 2018

Preprint

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The life cycle of the malaria parasite Plasmodium falciparum is tightly regulated, oscillating between stages of intense proliferation and quiescence. Cyclic 48-hour asexual replication of Plasmodium is markedly different from cell division in higher eukaryotes, and mechanistically poorly understood. Here, we report tight synchronisation of malaria parasites during the early phases of its cell cycle by exposure to DL-α-difluoromethylornithine (DFMO), which results in the depletion of polyamines. This induces an inescapable cell cycle arrest in G 1 (~15 hours post-invasion) by blocking G 1 /S transition. Cell cycle-arrested parasites enter a quiescent G 0 -like state but, upon addition of exogenous polyamines, re-initiate their cell cycle in a coordinated fashion. This ability to halt malaria parasites at a specific point in their cell cycle, and to subsequently trigger re-entry into the cell cycle, provides a valuable framework to investigate cell cycle regulation in these parasites. We therefore used gene expression analyses to show that re-entry into the cell cycle involves expression of Ca 2+ -sensitive (cdpk4 and pk2) and mitotic kinases (nima and ark2), with deregulation of the pre-replicative complex associated with expression of pk2. Changes in gene expression could be driven through transcription factors MYB1 and two ApiAP2 family members. This new approach to parasite synchronisation therefore expands our currently limited toolkit to investigate cell cycle regulation in malaria parasites.

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“…Taken together, our observations suggest a key role for translesion polymerases in diversification of malaria parasite antigens. In model eukaryotes, these enzymes interface with nucleotide excision (29), base excision (30), and mismatch repair pathways (30), which are thought to be a major source of mutations leading to drug resistance in naturally circulating malaria parasites (31)(32)(33)(34). Translesion polymerases may therefore play an underappreciated role in the continued threat of malaria to human health globally.…”

mentioning

confidence: 99%

Evolution of Host Specificity by Malaria Parasites through Altered Mechanisms Controlling Genome Maintenance

Siao

Borner

Perkins

et al. 2020

mBio

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The protozoan parasites that cause malaria infect a wide variety of vertebrate hosts, including birds, reptiles, and mammals, and the evolutionary pressures inherent to the host-parasite relationship have profoundly shaped the genomes of both host and parasite. Here, we report that these selective pressures have resulted in unexpected alterations to one of the most basic aspects of eukaryotic biology, the maintenance of genome integrity through DNA repair. Malaria parasites that infect humans continuously generate genetic diversity within their antigen-encoding gene families through frequent ectopic recombination between gene family members, a process that is a crucial feature of the persistence of malaria globally. The continuous generation of antigen diversity ensures that different parasite isolates are antigenically distinct, thus preventing extensive cross-reactive immunity and enabling parasites to maintain stable transmission within human populations. However, the molecular basis of the recombination between gene family members is not well understood. Through computational analyses of the antigen-encoding, multicopy gene families of different Plasmodium species, we report the unexpected observation that malaria parasites that infect rodents do not display the same degree of antigen diversity as observed in Plasmodium falciparum and appear to undergo significantly less ectopic recombination. Using comparative genomics, we also identify key molecular components of the diversification process, thus shedding new light on how malaria parasites balance the maintenance of genome integrity with the requirement for continuous genetic diversification. IMPORTANCE Malaria remains one of the most prevalent and deadly infectious diseases of the developing world, causing approximately 228 million clinical cases and nearly half a million deaths annually. The disease is caused by protozoan parasites of the genus Plasmodium, and of the five species capable of infecting humans, infections with P. falciparum are the most severe. In addition to the parasites that infect people, there are hundreds of additional species that infect birds, reptiles, and other mammals, each exquisitely evolved to meet the specific challenges inherent to survival within their respective hosts. By comparing the unique strategies that each species has evolved, key insights into host-parasite interactions can be gained, including discoveries regarding the pathogenesis of human disease. Here, we describe the surprising observation that closely related parasites with different hosts have evolved remarkably different methods for repairing their genomes. This observation has important implications for the ability of parasites to maintain chronic infections and for the development of host immunity.

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DNA damage regulation and its role in drug-related phenotypes in the malaria parasites

Cited by 68 publications

References 89 publications

Plasmodium falciparum Apn1 homolog is a mitochondrial base excision repair protein with restricted enzymatic functions

Plasmodium falciparum Apn1 homolog is a mitochondrial base excision repair protein with restricted enzymatic functions

Inducing controlled cell cycle arrest and re-entry during asexual proliferation ofPlasmodium falciparummalaria parasites

Evolution of Host Specificity by Malaria Parasites through Altered Mechanisms Controlling Genome Maintenance

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