Gupta Devendra Kumar, Patra Alok Tanala, Zhu Lei, Gupta Archana Patkar, Bozdech Zbynek
School of Biological Sciences, Nanyang Technological University, 639798, Singapore.
Sci Rep. 2016 Apr 1;6:23603. doi: 10.1038/srep23603.
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.
疟原虫恶性疟原虫的DNA在其于蚊子和人类宿主体内的复杂生命周期中，会遭受极高水平的基因毒性损伤。因此，DNA修复机制的大多数成分在寄生虫基因组中是保守的。在此，我们研究了恶性疟原虫对DNA损伤剂的全基因组反应，并提供了双链断裂和切除修复系统存在的转录证据。我们还表明，H3K9、H4K8和H3K56处的乙酰化在对烷基化剂甲磺酸甲酯（MMS）诱导的DNA损伤的直接和间接反应中发挥作用。青蒿素，一线抗疟化疗药物，与MMS相比引发了类似的反应，这表明其作为DNA损伤剂的活性。此外，与野生型恶性疟原虫相比，先前显示具有突变体表型的两个菌株（Dd2和W2）在MMS诱导的DNA损伤后未能诱导其DNA修复。对这两个突变体菌株的基因组测序确定了18个DNA修复基因中的点突变，这可能导致了这种现象。
