Characterization of the dual role of Plasmodium falciparum DNA methyltransferase in regulating transcription and translation.
Characterization of the dual role of Plasmodium falciparum DNA methyltransferase in regulating transcription and translation.
复制标题
DOI：
10.1093/nar/gkad248
复制
发表时间：
2023-05-08
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
--
作者：
DNA修饰在微调模式生物的生物过程中至关重要。然而，胞嘧啶甲基化（5 mC）的存在和假定的DNA甲基转移酶，PfDNMT 2，在人类疟疾病原体，恶性疟原虫的功能，仍然存在争议。在这里，我们重新审视了寄生虫基因组中的5 mC和PfDNMT 2的功能。在无性发育过程中低水平的基因组5 mC（0.1-0.2%），使用灵敏的质谱程序进行了鉴定。天然PfDNMT 2显示出显著的DNA甲基化活性，并且PfDNMT 2的破坏或过表达分别导致基因组5 mC水平降低或升高。PfDNMT 2破坏导致增殖表型增加，寄生虫具有延长的前体阶段并产生更高数量的后代。与PfDNMT 2与含有AP 2结构域的转录因子的相互作用一致，转录组学分析显示PfDNMT 2破坏导致许多基因表达的急剧改变，其中一些基因提供了PfDNMT 2破坏后增强增殖的分子基础。此外，PfDNMT 2破坏后，tRNAAsp水平及其C38位甲基化率以及含有天冬氨酸重复序列的报告基因的翻译显著降低，而PfDNMT 2互补后，tRNAAsp水平及其C38位甲基化恢复。我们的研究揭示了PfDNMT 2在恶性疟原虫无性发育过程中的双重功能。
DNA modifications are critical in fine-tuning the biological processes in model organisms. However, the presence of cytosine methylation (5mC) and the function of the putative DNA methyltransferase, PfDNMT2, in the human malaria pathogen, Plasmodium falciparum, remain controversial. Here, we revisited the 5mC in the parasite genome and the function of PfDNMT2. Low levels of genomic 5mC (0.1–0.2%) during asexual development were identified using a sensitive mass spectrometry procedure. Native PfDNMT2 displayed substantial DNA methylation activities, and disruption or overexpression of PfDNMT2 resulted in reduced or elevated genomic 5mC levels, respectively. PfDNMT2 disruption led to an increased proliferation phenotype, with the parasites having an extended schizont stage and producing a higher number of progenies. Consistent with PfDNMT2’s interaction with an AP2 domain-containing transcription factor, transcriptomic analyses revealed that PfDNMT2 disruption led to a drastic alteration in the expression of many genes, some of which provided the molecular basis of enhanced proliferation after PfDNMT2 disruption. Furthermore, levels of tRNAAsp and its methylation rate at position C38, and the translation of a reporter containing an aspartate repeat were significantly reduced after PfDNMT2 disruption, while the levels of tRNAAsp and its C38 methylation were restored after complementation of PfDNMT2. Our study sheds new light on the dual function of PfDNMT2 during P. falciparum asexual development.
登录
查看更多内容
影响因子：
4.4
作者：
Broadbent KM;Broadbent JC;Ribacke U;Wirth D;Rinn JL;Sabeti PC
通讯作者：
Sabeti PC
影响因子：
9.6
作者：
Batugedara G;Lu XM;Bunnik EM;Le Roch KG
通讯作者：
Le Roch KG
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
14.9
作者：
Balaji S;Babu MM;Iyer LM;Aravind L
通讯作者：
Aravind L