About half the world's population is at risk of malaria, with Plasmodium falciparum malaria being responsible for the most malaria related deaths globally. Antimalarial drugs such as chloroquine and artemisinin are directed towards the proliferating intra-erythrocytic stages of the parasite, which is responsible for all the clinical symptoms of the disease. These antimalarial drugs have been reported to function via multiple pathways, one of which induces DNA damage via the generation of free radicals and reactive oxygen species. An urgent need to understand the mechanistic details of drug response and resistance is highlighted by the decreasing clinical efficacy of the front line drug, Artemisinin. The replication factor C subunit 1 protein is an important component of the DNA replication machinery and DNA damage response mechanism. Here we show the translocation of PfRFC1 from an intranuclear localization to the nuclear periphery indicating an orchestrated progression of distinct patterns of replication in the developing parasites. PfRFC1 responds to genotoxic stress via elevated protein levels in soluble and chromatin bound fractions. Reduction of PfRFC1 protein levels upon treatment with antimalarials suggests an interplay of replication and DNA repair pathways leading to cell death. Additionally, mislocalization of the endogenously tagged protein confirmed its essential role in parasites' replication and DNA repair. This study provides key insights into DNA replication, DNA damage response and cell death in Plasmodium falciparum.

中文翻译：

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恶性疟原虫复制因子C亚基1参与遗传毒性应激反应

约有一半的世界人口患疟疾，恶性疟原虫疟疾是导致全球与疟疾相关的死亡人数最多的原因。抗疟药，例如氯喹和青蒿素，针对寄生虫的红细胞生成期，这是该疾病的所有临床症状的原因。这些抗疟药据报道可通过多种途径起作用，其中一种途径是通过自由基和活性氧的产生诱导DNA损伤。前线药物青蒿素的临床疗效不断下降突显了迫切需要了解药物反应和耐药性的机制细节。复制因子C亚基1蛋白是DNA复制机制和DNA损伤反应机制的重要组成部分。在这里，我们显示PfRFC1从核内定位到核外围的易位，表明在发育中的寄生虫中不同复制模式的精心策划的进展。PfRFC1通过提高可溶性和染色质结合部分中的蛋白质水平来响应遗传毒性胁迫。抗疟疾药物治疗后PfRFC1蛋白水平的降低表明复制和DNA修复途径相互作用会导致细胞死亡。此外，内源标记蛋白的错误定位证实了其在寄生虫复制和DNA修复中的重要作用。这项研究提供了有关DNA复制，DNA损伤反应和细胞死亡的关键见解。PfRFC1通过提高可溶性和染色质结合部分中的蛋白质水平来响应遗传毒性胁迫。抗疟疾药物治疗后PfRFC1蛋白水平的降低表明复制和DNA修复途径相互作用会导致细胞死亡。此外，内源标记蛋白的错误定位证实了其在寄生虫复制和DNA修复中的重要作用。这项研究提供了有关DNA复制，DNA损伤反应和细胞死亡的关键见解。PfRFC1通过提高可溶性和染色质结合部分中的蛋白质水平来响应遗传毒性胁迫。抗疟药治疗后PfRFC1蛋白水平的降低表明复制和DNA修复途径相互作用会导致细胞死亡。此外，内源标记蛋白的错误定位证实了其在寄生虫复制和DNA修复中的重要作用。这项研究提供了有关DNA复制，DNA损伤反应和细胞死亡的关键见解。恶性疟原虫。