Nuclear DNA replication and repair in parasites of the genus<i>Leishmania</i>: Exploiting differences to develop innovative therapeutic approaches

Uzcanga, Graciela L.; Lara, Eliana Higuera; Gutiérrez, Fernanda; Beaty, Doyle; Beske, Timo; Teran, Rommy; Navarro, Juan Carlos; Pasero, Philippe; Benítez, Washington; Poveda, Ana

doi:10.1080/1040841x.2016.1188758

Cited by 14 publications

(10 citation statements)

References 182 publications

(246 reference statements)

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“…Se han establecido dos familias de topoisomerasas, las de tipo I y las de tipo II, cuyo mecanismo de acción difiere, lo cual podría tener un valor agregado de diferenciación taxonómica en Leishmania spp. dada su variabilidad genética (25,26).…”

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Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi

Arrivillaga-Henríquez

Enríquez

Romero

et al. 2017

biomedica

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Introducción. La provincia de Pichincha, Ecuador, es un área endémica de leishmaniasis cutánea, en donde se han determinado como vectores los flebotomíneos antropofílicos con infección natural por Leishmania spp. Sin embargo, no se ha evaluado el papel en la transmisión de las especies zoofílicas.Objetivo. Evaluar la infección natural por Leishmania en dos especies de flebotomíneos zoofílicos, Lutzomyia reburra y Lu. barrettoi majuscula, y en una antropofílica, Lu. trapidoi, así como la endofagia y la sinantropía de estas especies en el noroccidente de Pichincha.Materiales y métodos. Los flebotomíneos se recolectaron en trampas de luz CDC colocadas en diferentes hábitats y altitudes en sitios que son focos de leishmaniasis cutánea. La infección con Leishmania spp. se detectó en el ADN genómico de hembras de las especies de flebotomíneos de interés. Se amplificó el gen espaciador interno de la transcripción del ARN ribosómico, unidad I (ITS1), y los genes de las topoiso-merasas mitocondrial II (mtTOPOII) y nuclear II (TopoII). Se determinaron los porcentajes de positividad para Leishmania a escala espaciotemporal, la proporción de endofagia y el índice de sinantropía.Resultados. Se determinó la presencia de infección natural por Le. amazonensis en Lu. reburra (9,5 %) y Lu. b. majuscula (23,8 %); en Lu. trapidoi se detectaron Le. amazonensis, Le. brazilienis y Le. naiffi-lainsoni. Los flebotomíneos eran asinantrópicos y con baja endofagia.Conclusión. Se registró por primera vez la presencia de infección natural en Lu. reburra y Lu. barrettoi majuscula por Le. amazonensis, y se demostró la importancia de los flebotomíneos zoofílicos en el mantenimiento del ciclo de transmisión de Leishmania spp. en focos endémicos.

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Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi

Arrivillaga-Henríquez

Enríquez

Romero

et al. 2017

biomedica

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“…With orthologs of several of the conserved eukaryotic replication proteins being identified in trypanosomatids, DNA replication in trypanosomes seems to broadly resemble that of other eukaryotes. However, that trypanosomatids diverged from other eukaryotes very early on is reflected in the fact that some of the conserved replication proteins are absent [14][15][16]. While most components of the replication elongation machinery including Mcm2-7, Cdc45, GINS, the DNA polymerases, and PCNA are present [14,[17][18][19][20][21], the same is not the case with components of the pre-replication complex.…”

Section: Introductionmentioning

confidence: 99%

DNA replication protein Cdc45 directly interacts with PCNA via its PIP box in Leishmania donovani and the Cdc45 PIP box is essential for cell survival

et al. 2020

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DNA replication protein Cdc45 is an integral part of the eukaryotic replicative helicase whose other components are the Mcm2-7 core, and GINS. We identified a PIP box motif in Leishmania donovani Cdc45. This motif is typically linked to interaction with the eukaryotic clamp proliferating cell nuclear antigen (PCNA). The homotrimeric PCNA can potentially bind upto three different proteins simultaneously via a loop region present in each monomer. Multiple binding partners have been identified from among the replication machinery in other eukaryotes, and the concerted /sequential binding of these partners are central to the fidelity of the replication process. Though conserved in Cdc45 across Leishmania species and Trypanosoma cruzi, the PIP box is absent in Trypanosoma brucei Cdc45. Here we investigate the possibility of Cdc45-PCNA interaction and the role of such an interaction in the in vivo context. Having confirmed the importance of Cdc45 in Leishmania DNA replication we establish that Cdc45 and PCNA interact stably in whole cell extracts, also interacting with each other directly in vitro. The interaction is mediated via the Cdc45 PIP box. This PIP box is essential for Leishmania survival. The importance of the Cdc45 PIP box is also examined in Schizosaccharomyces pombe, and it is found to be essential for cell survival here as well. Our results implicate a role for the Leishmania Cdc45 PIP box in recruiting or stabilizing PCNA on chromatin. The Cdc45-PCNA interaction might help tether PCNA and associated replicative DNA polymerase to the DNA template, thus facilitating replication fork elongation. Though multiple replication proteins that associate with PCNA have been identified in other eukaryotes, this is the first report demonstrating a direct interaction between Cdc45 and PCNA, and while our analysis suggests the interaction may not occur in human cells, it indicates that it may not be confined to trypanosomatids.

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“…Generally, studies on Leishmania replication focus on quantitative microscopy, timings of cell cycle phases, phase-contrast microscopy, fluorescence, and biophysical studies of cultured promastigotes (12)(13)(14) . Recent studies in the genus correlate genomic alteration to Leishmania replication and molecular mechanisms and factors involved in the regulation of DNA replication and repair (15)(16)(17)(18) .…”

Section: Resultsmentioning

confidence: 99%

“…The replicative DNA polymerases belonging to the B family are conserved in Leishmania spp. (18) . They are concerned with synthesis of DNA during elongation (31) .…”

Section: Resultsmentioning

confidence: 99%

Evidence-based insights on Leishmania replication and cytokinesis

Azab

Mawla

2018

Parasitologists United Journal

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Nuclear DNA replication and repair in parasites of the genusLeishmania: Exploiting differences to develop innovative therapeutic approaches

Abstract: (2017) Nuclear DNA replication and repair in parasites of the genus Leishmania: Exploiting differences to develop innovative therapeutic approaches, Critical Reviews in Microbiology, 43:2, 156-177,

Cited by 14 publications

References 182 publications

Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi

Eco-epidemiological aspects, natural detection and molecular identification of Leishmania spp. in Lutzomyia reburra, Lutzomyia barrettoi majuscula and Lutzomyia trapidoi

DNA replication protein Cdc45 directly interacts with PCNA via its PIP box in Leishmania donovani and the Cdc45 PIP box is essential for cell survival

Evidence-based insights on Leishmania replication and cytokinesis

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