DNA damage regulation and its role in drug-related phenotypes in the malaria parasites
DNA damage regulation and its role in drug-related phenotypes in the malaria parasites
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DOI：
10.1038/srep23603
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发表时间：
2016-04-01
影响因子：
4.6
通讯作者：
Bozdech, Zbynek
中科院分区：
文献类型：
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作者：
Gupta, Devendra Kumar;Patra, Alok Tanala;Bozdech, Zbynek
疟疾寄生虫恶性疟原虫的DNA在其在蚊子和人类宿主体内的复杂生命周期中受到异常高水平的基因毒性损伤。因此，大多数DNA修复机制的组成部分在寄生虫基因组中是保守的。在这里，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。我们还发现，H3K9、H4K8和H3K56位点的乙酰化在烷基化剂甲基磺酸盐（MMS）诱导的DNA损伤的直接和间接反应中起作用。与MMS相比，一线抗疟化疗药物青蒿素引起了类似的反应，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，先前显示出突变表型的两种菌株（Dd2和W2）在mms诱导的DNA损伤后无法诱导其DNA修复。两个突变菌株的基因组测序鉴定出18个DNA修复基因的点突变，这可能是导致这种现象的原因。
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.