Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>

ABSTRACT The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells, where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double-stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR), due t...

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Autores principales:	Susannah F. Calhoun, Jake Reed, Noah Alexander, Christopher E. Mason, Kirk W. Deitsch, Laura A. Kirkman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Plasmodium falciparum chromosome stability de novo telomere addition gene conversion homologous recombination telomere healing Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ed4d29f4bee646ababc123c1ab14efe7
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spelling	oai:doaj.org-article:ed4d29f4bee646ababc123c1ab14efe72021-11-15T15:51:44ZChromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>10.1128/mBio.00547-172150-7511https://doaj.org/article/ed4d29f4bee646ababc123c1ab14efe72017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00547-17https://doaj.org/toc/2150-7511ABSTRACT The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells, where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double-stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR), due to a lack of efficient nonhomologous end joining. However, given that the parasite is haploid during this stage of its life cycle, the mechanisms involved in maintaining genome stability are poorly understood. Of particular interest are the subtelomeric regions of the chromosomes, which contain the majority of the multicopy variant antigen-encoding genes responsible for virulence and disease severity. Here, we show that parasites utilize a competitive balance between de novo telomere addition, also called “telomere healing,” and HR to stabilize chromosome ends. Products of both repair pathways were observed in response to DSBs that occurred spontaneously during routine in vitro culture or resulted from experimentally induced DSBs, demonstrating that both pathways are active in repairing DSBs within subtelomeric regions and that the pathway utilized was determined by the DNA sequences immediately surrounding the break. In combination, these two repair pathways enable parasites to efficiently maintain chromosome stability while also contributing to the generation of genetic diversity. IMPORTANCE Malaria is a major global health threat, causing approximately 430,000 deaths annually. This mosquito-transmitted disease is caused by Plasmodium parasites, with infection with the species Plasmodium falciparum being the most lethal. Mechanisms underlying DNA repair and maintenance of genome integrity in P. falciparum are not well understood and represent a gap in our understanding of how parasites survive the hostile environment of their vertebrate and insect hosts. Our work examines DNA repair in real time by using single-molecule real-time (SMRT) sequencing focused on the subtelomeric regions of the genome that harbor the multicopy gene families important for virulence and the maintenance of infection. We show that parasites utilize two competing molecular mechanisms to repair double-strand breaks, homologous recombination and de novo telomere addition, with the pathway used being determined by the surrounding DNA sequence. In combination, these two pathways balance the need to maintain genome stability with the selective advantage of generating antigenic diversity.Susannah F. CalhounJake ReedNoah AlexanderChristopher E. MasonKirk W. DeitschLaura A. KirkmanAmerican Society for MicrobiologyarticlePlasmodium falciparumchromosome stabilityde novo telomere additiongene conversionhomologous recombinationtelomere healingMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium falciparum chromosome stability de novo telomere addition gene conversion homologous recombination telomere healing Microbiology QR1-502
spellingShingle	Plasmodium falciparum chromosome stability de novo telomere addition gene conversion homologous recombination telomere healing Microbiology QR1-502 Susannah F. Calhoun Jake Reed Noah Alexander Christopher E. Mason Kirk W. Deitsch Laura A. Kirkman Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
description	ABSTRACT The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells, where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double-stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR), due to a lack of efficient nonhomologous end joining. However, given that the parasite is haploid during this stage of its life cycle, the mechanisms involved in maintaining genome stability are poorly understood. Of particular interest are the subtelomeric regions of the chromosomes, which contain the majority of the multicopy variant antigen-encoding genes responsible for virulence and disease severity. Here, we show that parasites utilize a competitive balance between de novo telomere addition, also called “telomere healing,” and HR to stabilize chromosome ends. Products of both repair pathways were observed in response to DSBs that occurred spontaneously during routine in vitro culture or resulted from experimentally induced DSBs, demonstrating that both pathways are active in repairing DSBs within subtelomeric regions and that the pathway utilized was determined by the DNA sequences immediately surrounding the break. In combination, these two repair pathways enable parasites to efficiently maintain chromosome stability while also contributing to the generation of genetic diversity. IMPORTANCE Malaria is a major global health threat, causing approximately 430,000 deaths annually. This mosquito-transmitted disease is caused by Plasmodium parasites, with infection with the species Plasmodium falciparum being the most lethal. Mechanisms underlying DNA repair and maintenance of genome integrity in P. falciparum are not well understood and represent a gap in our understanding of how parasites survive the hostile environment of their vertebrate and insect hosts. Our work examines DNA repair in real time by using single-molecule real-time (SMRT) sequencing focused on the subtelomeric regions of the genome that harbor the multicopy gene families important for virulence and the maintenance of infection. We show that parasites utilize two competing molecular mechanisms to repair double-strand breaks, homologous recombination and de novo telomere addition, with the pathway used being determined by the surrounding DNA sequence. In combination, these two pathways balance the need to maintain genome stability with the selective advantage of generating antigenic diversity.
format	article
author	Susannah F. Calhoun Jake Reed Noah Alexander Christopher E. Mason Kirk W. Deitsch Laura A. Kirkman
author_facet	Susannah F. Calhoun Jake Reed Noah Alexander Christopher E. Mason Kirk W. Deitsch Laura A. Kirkman
author_sort	Susannah F. Calhoun
title	Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
title_short	Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
title_full	Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
title_fullStr	Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
title_full_unstemmed	Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>
title_sort	chromosome end repair and genome stability in <italic toggle="yes">plasmodium falciparum</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/ed4d29f4bee646ababc123c1ab14efe7
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Chromosome End Repair and Genome Stability in <italic toggle="yes">Plasmodium falciparum</italic>

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