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Chromosome End Repair and Genome Stability in .

TitleChromosome End Repair and Genome Stability in .
Publication TypeJournal Article
Year of Publication2017
AuthorsCalhoun SF, Reed J, Alexander N, Mason CE, Deitsch KW, Kirkman LA
JournalmBio
Volume8
Issue4
Date Published2017 08 08
ISSN2150-7511
KeywordsAnimals, Antigenic Variation, Chromosomes, DNA Breaks, Double-Stranded, DNA Damage, Gene Conversion, Genetic Variation, Genome, Protozoan, Genomic Instability, Homologous Recombination, Humans, Plasmodium falciparum, Sequence Analysis, DNA, Telomere
Abstract

The human malaria parasite 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 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 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. Malaria is a major global health threat, causing approximately 430,000 deaths annually. This mosquito-transmitted disease is caused by parasites, with infection with the species being the most lethal. Mechanisms underlying DNA repair and maintenance of genome integrity in 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 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.

DOI10.1128/mBio.00547-17
Alternate JournalmBio
PubMed ID28790200
PubMed Central IDPMC5550746
Grant ListK08 AI076635 / AI / NIAID NIH HHS / United States
R01 AI052390 / AI / NIAID NIH HHS / United States
R01 AI099327 / AI / NIAID NIH HHS / United States

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