DNA damage regulation and its role in drug-related phenotypes in the malaria parasites.
Ontology highlight
ABSTRACT:
ORGANISM(S): Plasmodium falciparum
PROVIDER: GSE72580 | GEO | 2016/06/01
SECONDARY ACCESSION(S): PRJNA294407
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-01 | E-GEOD-72580 | biostudies-arrayexpress
Project description:DNA of malaria parasites, Plasmodium falciparum, is subjected to extraordinary high levels of genotoxic insults during its complex life cycle within both the mosquito and human host. Accordingly, most of the components of DNA repair machinery are conserved in the parasite genome. Here, we investigated the genome-wide responses of P. falciparum to DNA damaging agents and provided transcriptional evidence of the existence of the double strand break and excision repair system. We also showed that acetylation at H3K9, H4K8, and H3K56 play a role in the direct and indirect response to DNA damage induced by an alkylating agent, methyl methanesulphonate (MMS). Artemisinin, the first line antimalarial chemotherapeutics elicits a similar response compared to MMS which suggests its activity as a DNA damaging agent. Moreover, in contrast to the wild-type P. falciparum, two strains (Dd2 and W2) previously shown to exhibit a mutator phenotype, fail to induce their DNA repair upon MMS-induced DNA damage. Genome sequencing of the two mutator strains identified point mutations in 18 DNA repair genes which may contribute to this phenomenon.
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Project description:The goal of our study is to characterize the global transcriptional resposne of P.falciparum to DNA damageing agents. Alongside, we stidied the epigenetic regulation of DNA damage resposne in parasite. Further, we studied the mecanism which underlined the ARMD (mutator) phenotype of P. falciparum. In order to elucidate the transcriptiona resposne to DNA damage, P. falciparum 3D7 parasites were treated with 4 perturbating agents for 6 hours. We mapped the global nucleosome occupancy for 3 most responsive histone modifications to DNA damage by chromatin immunoprecipitation coupled with DNA microarray (ChIP-on-chip). In order to identify the transcriptional similarities between artemesinin and MMS, we carried out 6 hours of artemesinin treatment in triplicates and compared with triplicate dataset of MMS.
2016-06-01 | E-GEOD-72578 | biostudies-arrayexpress
Project description:The goal of our study is to characterize the global transcriptional resposne of P.falciparum to DNA damageing agents. Alongside, we stidied the epigenetic regulation of DNA damage resposne in parasite. Further, we studied the mecanism which underlined the ARMD (mutator) phenotype of P. falciparum. In order to elucidate the transcriptiona resposne to DNA damage, P. falciparum 3D7 parasites were treated with 4 perturbating agents for 6 hours. We mapped the global nucleosome occupancy for 3 most responsive histone modifications to DNA damage by chromatin immunoprecipitation coupled with DNA microarray (ChIP-on-chip). In order to identify the transcriptional similarities between artemesinin and MMS, we carried out 6 hours of artemesinin treatment in triplicates and compared with triplicate dataset of MMS.
2016-06-01 | E-GEOD-72579 | biostudies-arrayexpress
Project description:The goal of our study is to characterize the global transcriptional resposne of P.falciparum to DNA damageing agents. Alongside, we stidied the epigenetic regulation of DNA damage resposne in parasite. Further, we studied the mecanism which underlined the ARMD (mutator) phenotype of P. falciparum.
2016-06-01 | GSE72578 | GEO
Project description:The goal of our study is to characterize the global transcriptional resposne of P.falciparum to DNA damageing agents. Alongside, we stidied the epigenetic regulation of DNA damage resposne in parasite. Further, we studied the mecanism which underlined the ARMD (mutator) phenotype of P. falciparum.
2016-06-01 | GSE72579 | GEO
Project description:DNA damage regulation and its role in drug-related phenotypes in the malaria parasites.
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Project description:Malaria remains a major cause of morbidity and mortality in the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double-strand breaks within subtelomeric regions. We observed that the process of telomere healing induces the initial synthesis of telomere repeats well in excess of the minimal number required for end stability. However, once stabilized, these newly created telomeres appear to function normally, eventually returning to a length nearing that of intact chromosome ends. These results parallel recent observations in humans, suggesting an evolutionarily conserved mechanism for chromosome end repair.
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Project description:Although the mechanisms by which malaria parasites develop resistance to drugs are unclear, current knowledge suggests a main mechanism of resistance is the alteration of target enzymes by point mutation. In other organisms, defects in DNA mismatch repair have been linked to increased mutation rates and drug resistance. We have identified an unusual complement of mismatch repair genes in the Plasmodium genome. An initial functional test of two of these genes (PfMSH2-1 and PfMSH2-2) using a dominant mutator assay showed an elevation in mutation frequency with the PfMSH2-2 homolog, indirectly demonstrating a role for this gene in mismatch repair. We successfully disrupted PbMSH2-2 in the Plasmodium berghei laboratory isolate NK65, and showed that this gene is not essential for parasite growth in either the asexual (rodent) or sexual (mosquito) stages of the lifecycle. Although we observed some differences in levels of drug resistance between wild type and mutant parasites, no uniform trend emerged and preliminary evidence does not support a strong link between PbMSH2-2 disruption and dramatically increased drug resistance. We found microsatellite polymorphism in the PbMSH2-2 disrupted parasites in less than 40 life cycles post-transfection, but not in PbMap2K disrupted controls or mosquito-passaged wild type parasites, which suggests a possible role for PbMSH2-2 in preventing microsatellite slippage, similar to MSH2 in other organisms. Our studies suggest that Plasmodium species may have evolved a unique variation on the highly conserved system of DNA repair compared to the mismatch repair systems in other eukaryotes.
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Project description:Dynamic changes in gene positioning contribute to differential expression of virulence-related gene families in protozoan pathogens; however, the role of nuclear architecture in gene expression in the human malaria parasite Plasmodium falciparum remains poorly understood. Here we investigated the developmentally regulated ribosomal RNA (rRNA) gene family in P. falciparum, which, unlike that in most eukaryotes, contains only a few unlinked copies of rRNA genes scattered over the subtelomeric regions of several chromosomes. We show that active and silent members of this gene family cluster in a single perinuclear nucleolus. This rDNA nuclear confinement is DNA sequence dependent, as plasmids carrying rDNA fragments are targeted to the nucleolus. Likewise, insertion of an rDNA sequence into a subtelomere from a chromosome lacking rRNA genes leads to repositioning in the nucleolus. Furthermore, we observed that rDNA spatial organization restricted interchromosomal interactions, as chromosome end-bearing rRNA genes were found to be preferentially juxtaposed, demonstrating nonrandom association of telomeres. Using Br-UTP incorporation, we observed two alpha-amanitin-resistant nucleolar transcription sites that disappeared when the rDNA cluster broke up in the replicative blood stages. Taken together, our results provide conceptual insights into functionally differentiated nuclear territories and their role in gene expression in malaria parasites.
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