The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations that are known to lead to adverse physiological outcomes. The apicoplast genome is particularly vulnerable to the harmful effects of 8oxodGTP due to very high AT content (~ 87%). We show that the proofreading activity of PfpPol has the unique ability to remove the oxidized nucleotide from the primer terminus. Due to this property, the proofreading domain of PfpPol is able to prevent mutagenesis of the AT-rich apicoplast genome and neutralize the deleterious genotoxic effects of ROS generated in the apicoplast due to normal metabolic processes. The proofreading activity of the Pfprex enzyme may, therefore, represent an attractive target for therapeutic intervention. Also, a survey of DNA repair pathways shows that the observed property of Pfprex constitutes a novel form of dynamic error correction wherein the repair of promutagenic damaged nucleotides is concomitant with DNA replication.

Pfprex 酶 (PfpPol) 的 DNA 聚合酶模块负责疟原虫顶质体细胞器基因组的复制。我们发现 PfpPol 可以错误地掺入氧化核苷酸，例如与 dA 相对的 8oxodGTP。该事件会引起颠换突变，已知会导致不良的生理结果。由于 AT 含量非常高 (~ 87%)，顶端质体基因组特别容易受到 8oxodGTP 的有害影响。我们证明 PfpPol 的校对活性具有独特的能力，可以去除引物末端的氧化核苷酸。由于这一特性，PfpPol 的校对结构域能够防止富含 AT 的顶端质体基因组的突变，并中和顶端质体中由于正常代谢过程而产生的 ROS 的有害基因毒性作用。因此，Pfprex 酶的校对活性可能代表治疗干预的一个有吸引力的目标。此外，对 DNA 修复途径的调查表明，观察到的 Pfprex 特性构成了一种新形式的动态纠错，其中促诱变受损核苷酸的修复与 DNA 复制同时进行。