title: DNA damage regulation and its role in drug-related phenotypes in the malaria parasites.
abstract: DNA of malaria parasites, Plasmodium falciparum, is subjected to extraordinary high levels of genotoxic insults during its complex life cycle within both the mosquito and human host. Accordingly, most of the components of DNA repair machinery are conserved in the parasite genome. Here, we investigated the genome-wide responses of P. falciparum to DNA damaging agents and provided transcriptional evidence of the existence of the double strand break and excision repair system. We also showed that acetylation at H3K9, H4K8, and H3K56 play a role in the direct and indirect response to DNA damage induced by an alkylating agent, methyl methanesulphonate (MMS). Artemisinin, the first line antimalarial chemotherapeutics elicits a similar response compared to MMS which suggests its activity as a DNA damaging agent. Moreover, in contrast to the wild-type P. falciparum, two strains (Dd2 and W2) previously shown to exhibit a mutator phenotype, fail to induce their DNA repair upon MMS-induced DNA damage. Genome sequencing of the two mutator strains identified point mutations in 18 DNA repair genes which may contribute to this phenomenon.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
authors.forename: Devendra Kumar
authors.initials: DK
authors.lastname: Gupta
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
authors.forename: Alok Tanala
authors.initials: AT
authors.lastname: Patra
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
authors.forename: Archana Patkar
authors.initials: AP
authors.lastname: Gupta
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Bozdech
mesh_terms: D000107:Acetylation; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D016054:DNA, Protozoan / Q000187:drug effects / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017125:Genes, Protozoan; D042421:Histone Code / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000633:toxicity; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002843:Chromatin; D016054:DNA, Protozoan; D006877:Hydroxamic Acids; D015800:Protozoan Proteins; C012589:trichostatin A; C031327:artemisinin; D008741:Methyl Methanesulfonate