Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum.
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum.
复制标题
DOI：
10.1186/s12864-018-5207-7
复制
发表时间：
2018-11-29
期刊：
影响因子：
4.4
通讯作者：
Jiang RHY
中科院分区：
文献类型：
--
作者：
Gibbons J;Button-Simons KA;Adapa SR;Li S;Pietsch M;Zhang M;Liao X;Adams JH;Ferdig MT;Jiang RHY
在东南亚，恶性疟原虫对一线抗疟药物青蒿素组合疗法中的青蒿素成分表现出耐药性。如果青蒿素耐药性（ART-R）蔓延到非洲，数百万人的生命将面临危险。PF3D7_1343700，“K13”螺旋桨区的单个非同义突变与抗性有关。在这项工作中，我们使用转录分析来表征实验室生成的k13插入突变体，该突变体先前被证明对青蒿素具有更高的敏感性，以探索k13的功能作用。一组RNA-seq和微阵列实验证实，k13的表达谱在突变红细胞内发育周期的早期环和早期滋养体阶段特异性改变。在这个突变体中，k13转录本在早期环阶段的下调与转录组向更像滋养体的状态推进有关。为了发现k13失调的具体下游效应，我们开发了一种新的计算方法来搜索差异基因表达，同时考虑转录的时间序列。我们发现转录组转移的最强生物学特征是在环发育早期DNA复制和修复基因的上调和在滋养体早期DNA复制和修复基因的下调；相比之下，管家基因的表达是不变的。由于k13失调，这种作用是拮抗的，因此k13水平与DNA复制和修复基因表达呈负相关。我们的研究结果支持k13作为应激反应调节因子的作用，这与青蒿素的作用模式是氧化应激的假设一致，k13作为Keap1的功能同源物，在人类中调节DNA复制和修复基因以响应氧化应激。本文的在线版本（10.1186/s12864-018-5207-7）包含补充材料，授权用户可以使用。
Plasmodium falciparum exhibits resistance to the artemisinin component of the frontline antimalarial treatment Artemisinin-based Combination Therapy in South East Asia. Millions of lives will be at risk if artemisinin resistance (ART-R) spreads to Africa. Single non-synonymous mutations in the propeller region of PF3D7_1343700,“K13” are implicated in resistance. In this work, we use transcriptional profiling to characterize a laboratory-generated k13 insertional mutant previously demonstrated to have increased sensitivity to artemisinins to explore the functional role of k13. A set of RNA-seq and microarray experiments confirmed that the expression profile of k13 is specifically altered during the early ring and early trophozoite stages of the mutant intraerythrocytic development cycle. The down-regulation of k13 transcripts in this mutant during the early ring stage is associated with a transcriptome advance towards a more trophozoite-like state. To discover the specific downstream effect of k13 dysregulation, we developed a new computational method to search for differential gene expression while accounting for the temporal sequence of transcription. We found that the strongest biological signature of the transcriptome shift is an up-regulation of DNA replication and repair genes during the early ring developmental stage and a down-regulation of DNA replication and repair genes during the early trophozoite stage; by contrast, the expressions of housekeeping genes are unchanged. This effect, due to k13 dysregulation, is antagonistic, such that k13 levels are negatively correlated with DNA replication and repair gene expression. Our results support a role for k13 as a stress response regulator consistent with the hypothesis that artemisinins mode of action is oxidative stress and k13 as a functional homolog of Keap1 which in humans regulates DNA replication and repair genes in response to oxidative stress. The online version of this article (10.1186/s12864-018-5207-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
6.7
作者：
Ganesan K;Ponmee N;Jiang L;Fowble JW;White J;Kamchonwongpaisan S;Yuthavong Y;Wilairat P;Rathod PK
通讯作者：
Rathod PK
影响因子：
14.9
作者：
Kanehisa M;Goto S;Sato Y;Furumichi M;Tanabe M
通讯作者：
Tanabe M
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：
6.7
作者：
Campbell TL;De Silva EK;Olszewski KL;Elemento O;Llinás M
通讯作者：
Llinás M
影响因子：
3
作者：
Lubell Y;Dondorp A;Guérin PJ;Drake T;Meek S;Ashley E;Day NP;White NJ;White LJ
通讯作者：
White LJ