Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum
Abstract Background 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 mu...
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doaj-61e03efb695f4bd0ad5c8b1ab6e0e5ce2020-11-25T01:32:27ZengBMCBMC Genomics1471-21642018-11-0119111410.1186/s12864-018-5207-7Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparumJustin Gibbons0Katrina A. Button-Simons1Swamy R. Adapa2Suzanne Li3Maxwell Pietsch4Min Zhang5Xiangyun Liao6John H. Adams7Michael T. Ferdig8Rays H. Y. Jiang9Department of Molecular Medicine, Morsani College of Medicine, University of South FloridaEck Institute for Global Health, Department of Biological Sciences, University of Notre DameCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaDepartment of Computer Science & Engineering, University of South FloridaCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaEck Institute for Global Health, Department of Biological Sciences, University of Notre DameCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South FloridaAbstract Background 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. Results 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. Conclusion 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.http://link.springer.com/article/10.1186/s12864-018-5207-7MalariaArtemisininK13Drug-resistance |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Justin Gibbons Katrina A. Button-Simons Swamy R. Adapa Suzanne Li Maxwell Pietsch Min Zhang Xiangyun Liao John H. Adams Michael T. Ferdig Rays H. Y. Jiang |
spellingShingle |
Justin Gibbons Katrina A. Button-Simons Swamy R. Adapa Suzanne Li Maxwell Pietsch Min Zhang Xiangyun Liao John H. Adams Michael T. Ferdig Rays H. Y. Jiang Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum BMC Genomics Malaria Artemisinin K13 Drug-resistance |
author_facet |
Justin Gibbons Katrina A. Button-Simons Swamy R. Adapa Suzanne Li Maxwell Pietsch Min Zhang Xiangyun Liao John H. Adams Michael T. Ferdig Rays H. Y. Jiang |
author_sort |
Justin Gibbons |
title |
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum |
title_short |
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum |
title_full |
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum |
title_fullStr |
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum |
title_full_unstemmed |
Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum |
title_sort |
altered expression of k13 disrupts dna replication and repair in plasmodium falciparum |
publisher |
BMC |
series |
BMC Genomics |
issn |
1471-2164 |
publishDate |
2018-11-01 |
description |
Abstract Background 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. Results 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. Conclusion 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. |
topic |
Malaria Artemisinin K13 Drug-resistance |
url |
http://link.springer.com/article/10.1186/s12864-018-5207-7 |
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