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Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum

ABSTRACT: Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum

PROVIDER: PRJNA488554 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7768630_1.fastq.gz	Fastqsanger.gz
	SRR7768630_2.fastq.gz	Fastqsanger.gz
	SRR7768640_1.fastq.gz	Fastqsanger.gz
	SRR7768640_2.fastq.gz	Fastqsanger.gz
	SRR7768650_1.fastq.gz	Fastqsanger.gz

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Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum

Project description:Background: Plasmodium falciparum has evolved 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 resistance 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 in this mutant during the early ring stage is associated with a transcriptome shift 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: Because a hypothesized mode of action of artemisinins is oxidative stress our results support a role for k13 as a stress response regulator, consistent with the role of its human homolog Keap1, that regulates DNA replication and repair genes in response to oxidative stress.

2018-10-25 | GSE119231 | GEO

Plasmodium falciparum intraerythrocytic stage transcription time course for NF54 and isogenic mutant line with altered K13 expression I.

Project description:Plasmodium falciparum intraerythrocytic stage transcription four hour time course for NF54 and PB58 (an isogenic line with a piggyBac transposon in the 5’ UTR of K13 of K13 that alters K13 expression).

2018-10-28 | GSE119514 | GEO

Plasmodium falciparum intraerythrocytic stage transcription time course for NF54 and isogenic mutant line with altered K13 expression II.

2023-06-01 | GSE119516 | GEO

Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum.

Project description:BackgroundPlasmodium 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.ResultsA 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.ConclusionOur 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.

| S-EPMC6263542 | biostudies-literature

K13 580Y allele not linked to increased P. falciparum recrudescences in artesunate-treated Aotus

Project description:Concerns about impending failure of artemisinin compounds (ART) have grown with global use of ART-based combination therapy (ACT) against malaria. WHO has defined Plasmodium falciparum resistance to ART as prolonged parasite clearance half-life in vivo (t1/2) plus the presence of certain K13 Kelch-propeller substitutions, e.g. C580Y. Recrudescences and fever clearance times after ART monotherapy, however, have not correlated well with these criteria. We have crossed K13 C580 wild-type and 580Y-mutant parasites for ART studies in Aotus. Artesunate treated C580- but not 580Y-infections recrudesced requiring retreatment, and K13 type had little or no effect on t1/2. These results challenge K13 and t1/2 variations as markers of increased resistance to ART per se and emphasize the need for effective partner drugs in ACTs.

2019-02-11 | GSE78689 | GEO

Global RNA expression profiling of k13-edited mutant and isogenic wild-type Plasmodium falciparum malaria parasites during the parasite's intra-erythrocytic developmental cycle and the parasite's response to dihydroartemisinin (DHA).

Project description:K13 mutations are causal for artemisinin resistance in Plasmodium falciparum human malaria. The objective of our study is to characterize gene expression signatures associated with K13 mutations by comparing transcriptional profiles and response to DHA of K13 mutant (C580Y, R539T) and isogenic wild-type lines that were generated by zinc finger nuclease (ZFN) based editing in a long-term adapted (Dd2) and a contemporary laboratory-adapted clinical isolate (Cam3.II).

2020-11-01 | GSE151189 | GEO

Global protein quantification of changes in K13 mutant and isogenic wild-type P. falciparum parasites during the intra-erythrocytic developmental cycle

Project description:K13 mutations are causal for artemisinin resistance in Plasmodium falciparum human malaria. We characterized changes in protein abundance associated with K13 mutations during the parasite's 48h intra-erythrocytic developmental cycle by comparing protein expression profiles of K13 mutant (C580Y, R539T) and isogenic wild-type lines that were generated by zinc finger nuclease (ZFN) based editing in a laboratory-adapted clinical isolate (Cam3.II). For each parasite line, we harvested tightly synchronized ring and trophozoite parasites on two independent occasions, except for the C580Y line which was harvested only once at trophozoite stage.

2020-11-23 | PXD019612 | Pride

Replication origin mapping in the malaria parasite P. falciparum

Project description:Replication origin mapping in the malaria parasite Plasmodium falciparum

2022-08-04 | GSE210010 | GEO

Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

Project description:This SuperSeries is composed of the following subset Series: GSE25878: Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription (expression) GSE25879: Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription (CGH) Refer to individual Series

2010-12-07 | E-GEOD-25883 | biostudies-arrayexpress

Plasmodium falciparum intraerythrocytic stage transcription time course for NF54 and isogenic mutant line with altered K13 expression I.

Project description:Plasmodium falciparum intraerythrocytic stage transcription time course for NF54 and isogenic mutant line with altered K13 expression I.

| PRJNA489977 | ENA

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