Dataset Information

Homologous Recombination in Protozoan Parasites and Recombinase Inhibitors.

ABSTRACT: Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that utilizes a homologous template to fully repair the damaged DNA. HR is critical to maintain genome stability and to ensure genetic diversity during meiosis. A specialized class of enzymes known as recombinases facilitate the exchange of genetic information between sister chromatids or homologous chromosomes with the help of numerous protein accessory factors. The majority of the HR machinery is highly conserved among eukaryotes. In many protozoan parasites, HR is an essential DSB repair pathway that allows these organisms to adapt to environmental conditions and evade host immune systems through genetic recombination. Therefore, small molecule inhibitors, capable of disrupting HR in protozoan parasites, represent potential therapeutic options. A number of small molecule inhibitors were identified that disrupt the activities of the human recombinase RAD51. Recent studies have examined the effect of two of these molecules on the Entamoeba recombinases. Here, we discuss the current understandings of HR in the protozoan parasites Trypanosoma, Leishmania, Plasmodium, and Entamoeba, and we review the small molecule inhibitors known to disrupt human RAD51 activity.

SUBMITTER: Kelso AA

PROVIDER: S-EPMC5594099 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Homologous Recombination in Protozoan Parasites and Recombinase Inhibitors.

Kelso Andrew A AA Waldvogel Sarah M SM Luthman Adam J AJ Sehorn Michael G MG

Frontiers in microbiology 20170907

Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that utilizes a homologous template to fully repair the damaged DNA. HR is critical to maintain genome stability and to ensure genetic diversity during meiosis. A specialized class of enzymes known as recombinases facilitate the exchange of genetic information between sister chromatids or homologous chromosomes with the help of numerous protein accessory factors. The majority of the HR machinery is highly conserved a ...[more]

PMID: 28936205

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Project description:Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)-whose role is to facilitate proteostasis-play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille's heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

Project description:Parasitic food-borne diseases, particularly those caused by the protozoan parasites Cryptosporidium, Giardia, Cyclospora cayetanensis and Entamoeba are increasingly becoming common and have received considerable attention in the last two decades. The ability of the transmission stages of the parasites to survive in the environment for prolonged periods, globalization of the food industry and changes in eating habits have contributed to the numbers of human infections. This systematic scoping review highlights these important water- and foodborne parasites in the African context, detailing the burden in African water sources, wastewater/effluents and fresh produce. A scoping review search targeting African countries was conducted in Medline, Web of science and African journals online as well as back referencing from included studies covering the period 1990 to January 2020. Out of 1134 studies, 68 were included in the review. The articles covered 17 out of 54 African countries. There were 39/68 studies reporting on water sources while the rest reported on fresh produce. Cryptosporidium prevalence ranged from 6 to 100% in surface water, 4 to 100% in tap water and up to 100% in wastewater and sludge. In fresh produce, Cryptosporidium was reported from five countries with prevalence of 0.8–75%. Giardia was reported in 47 out of 68 articles; prevalence ranged from 2.4% in surface water; 1% to over 70% in tap water; 28–100% in wastewater and 2% - 99% in fresh produce. Prevalence of Cyclospora cayetanensis was lower. Prevalence of Entamoeba was 78% in surface water; 100% in wastewater and up to 99% in fresh produce. This study finds that Africa is no exception to the risk presented by the subject parasites from water and/or food sources. Routine screening for these parasites particularly at household level and provision of adequate and safe drinking water would help to control the parasites. Graphical abstract Unlabelled Image Highlights • African rural communities faced with clean water challenges.• African water bodies and sources contaminated with Cryptosporidium, Giardia, Cyclospora, and Entamoeba and other pathogens• Fresh produce are carriers of protozoan parasites Cryptosporidium, Giardia, Cyclospora, Entamoeba.

Dataset Information

Homologous Recombination in Protozoan Parasites and Recombinase Inhibitors.

Publications

Homologous Recombination in Protozoan Parasites and Recombinase Inhibitors.

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