Dataset Information

A Homolog of Structural Maintenance of Chromosome 1 Is a Persistent Centromeric Protein Which Associates With Nuclear Pore Components in Toxoplasma gondii.

ABSTRACT: Apicomplexa are obligate intracellular parasites which cause various animal and human diseases including malaria, toxoplasmosis, and cryptosporidiosis. They proliferate by a unique mechanism that combines physically separated semi-closed mitosis of the nucleus and assembly of daughter cells by internal budding. Mitosis occurs in the presence of a nuclear envelope and with little appreciable chromatin condensation. A long standing question in the field has been how parasites keep track of their uncondensed chromatin chromosomes throughout their development, and hence secure proper chromosome segregation during division. Past work demonstrated that the centromeres, the region of kinetochore assembly at chromosomes, of Toxoplasma gondii remain clustered at a defined region of the nuclear periphery proximal to the main microtubule organizing center of the cell, the centrosome. We have proposed that this mechanism is likely involved in the process. Here we set out to identify underlying molecular players involved in centromere clustering. Through pharmacological treatment and structural analysis we show that centromere clustering is not mediated by persistent microtubules of the mitotic spindle. We identify the chromatin binding factor a homolog of structural maintenance of chromosomes 1 (SMC1). Additionally, we show that both TgSMC1, and a centromeric histone, interact with TgExportin1, a predicted soluble component of the nuclear pore complex. Our results suggest that the nuclear envelope, and in particular the nuclear pore complex may play a role in positioning centromeres in T. gondii.

SUBMITTER: Francia ME

PROVIDER: S-EPMC7343853 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

A Homolog of Structural Maintenance of Chromosome 1 Is a Persistent Centromeric Protein Which Associates With Nuclear Pore Components in <i>Toxoplasma gondii</i>.

Francia Maria E ME Bhavsar Sheila S Ting Li-Min LM Croken Matthew M MM Kim Kami K Dubremetz Jean-Francois JF Striepen Boris B

Frontiers in cellular and infection microbiology 20200702

Apicomplexa are obligate intracellular parasites which cause various animal and human diseases including malaria, toxoplasmosis, and cryptosporidiosis. They proliferate by a unique mechanism that combines physically separated semi-closed mitosis of the nucleus and assembly of daughter cells by internal budding. Mitosis occurs in the presence of a nuclear envelope and with little appreciable chromatin condensation. A long standing question in the field has been how parasites keep track of their u ...[more]

PMID: 32714878

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Project description:The importance of maintaining the fidelity of the mitochondrial genome is underscored by the presence of various repair pathways within this organelle. Presumably, the repair of mitochondrial DNA would be of particular importance in organisms that possess only a single mitochondrion, like the human pathogens Plasmodium falciparum and Toxoplasma gondii. Understanding the machinery that maintains mitochondrial DNA in these parasites is of particular relevance, as mitochondrial function is a validated and effective target for anti-parasitic drugs. We previously determined that the Toxoplasma MutS homolog TgMSH1 localizes to the mitochondrion. MutS homologs are key components of the nuclear mismatch repair system in mammalian cells, and both yeast and plants possess MutS homologs that localize to the mitochondria where they regulate DNA stability. Here we show that the lack of TgMSH1 results in accumulation of single nucleotide variations in mitochondrial DNA and a reduction in mitochondrial DNA content. Additionally, parasites lacking TgMSH1 function can survive treatment with the cytochrome b inhibitor atovaquone. While the Tgmsh1 knockout strain has several missense mutations in cytochrome b, none affect amino acids known to be determinants of atovaquone sensitivity and atovaquone is still able to inhibit electron transport in the Tgmsh1 mutants. Furthermore, culture of Tgmsh1 mutant in the presence atovaquone leads to parasites with enhanced atovaquone resistance and complete shutdown of respiration. Thus, parasites lacking TgMSH1 overcome the disruption of mitochondrial DNA by adapting their physiology allowing them to forgo the need for oxidative phosphorylation. Consistent with this idea, the Tgmsh1 mutant is resistant to mitochondrial inhibitors with diverse targets and exhibits reduced ability to grow in the absence of glucose. This work shows TgMSH1 as critical for the maintenance and fidelity of the mitochondrial DNA in Toxoplasma, reveals a novel mechanism for atovaquone resistance, and exposes the physiological plasticity of this important human pathogen.

Dataset Information

A Homolog of Structural Maintenance of Chromosome 1 Is a Persistent Centromeric Protein Which Associates With Nuclear Pore Components in Toxoplasma gondii.

Publications

A Homolog of Structural Maintenance of Chromosome 1 Is a Persistent Centromeric Protein Which Associates With Nuclear Pore Components in <i>Toxoplasma gondii</i>.

Similar Datasets

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