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Overview of DNA Repair in Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major  [PDF]
Danielle Gomes Passos-Silva,Matheus Andrade Raj?o,Pedro Henrique Nascimento de Aguiar,Jo?o Pedro Vieira-da-Rocha,Carlos Renato Machado,Carolina Furtado
Journal of Nucleic Acids , 2010, DOI: 10.4061/2010/840768
Abstract: A wide variety of DNA lesions arise due to environmental agents, normal cellular metabolism, or intrinsic weaknesses in the chemical bonds of DNA. Diverse cellular mechanisms have evolved to maintain genome stability, including mechanisms to repair damaged DNA, to avoid the incorporation of modified nucleotides, and to tolerate lesions (translesion synthesis). Studies of the mechanisms related to DNA metabolism in trypanosomatids have been very limited. Together with recent experimental studies, the genome sequencing of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, three related pathogens with different life cycles and disease pathology, has revealed interesting features of the DNA repair mechanism in these protozoan parasites, which will be reviewed here. 1. Introduction The trypanosomatids Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major are the causative agents of Chagas disease, African sleeping sickness and leishmaniasis, respectively. These protozoan pathogens affect over 27 million people, primarily in developing countries within tropical and subtropical regions. There are no vaccines for these diseases and only a few drugs, which are largely ineffective due to toxicity and resistance [1]. These three pathogens (herein collectively referred to as Tritryps) share many general characteristics, especially the presence of the unique mitochondrion, which contains a dense region named as kinetoplast. This mitochondrial region is composed by a network of several thousand minicircles and a few dozen maxicircles that form the kinetoplast DNA (kDNA) [2]. Minicircles encode guide RNAs that modify maxicircle transcripts by RNA editing while maxicircles are correspondent to the mitochondrial DNA in higher eukaryotes that encodes rRNAs and the subunits of respiratory complexes [2]. The mitochondrion replicates its DNA, maintains its structural integrity, and undergoes division. Actually, kDNA replication always takes place earlier than mitosis, indicating that the kDNA may be needed for cell division, either by signaling a successful replication or by affecting the structure [3]. Furthermore, the trypanosome mitochondrion may hold vital metabolic pathways besides a possible role in Ca+2 homeostasis, fatty acid metabolism, and apoptosis [3]. In fact, kDNA function and integrity may play a crucial role in the survival of some stages of Tritryps lifecycles [3–5]. However, the kDNA is subjected to large amounts of endogenous oxidative damage generated by oxidative phosphorylation. Thus, an efficient kDNA maintenance mechanism is necessary
A new repetitive DNA sequence from Trypanosoma cruzi
Mendon?a-Lima, Leila de;Traub-Cseko, Yara M.;
Memórias do Instituto Oswaldo Cruz , 1991, DOI: 10.1590/S0074-02761991000400020
Abstract: tandemly repeated dna sequences are found in the genome of higher eukaryotes, and have also been demonstrated in trypanosoma cruzi. repeated dna sequences are potentially useful for the diagnostic detection of t. cruzi (a. gonzales et al., 1984, proc. natl. acad. sci. usa, 81: 3356-3360). we have isoleted two clones from a genomic library of t. cruzi (y strain) that contain, in one clone a family of at least seven copies of a repetitive sequence of approximately 600 base pairs, and in the other an independent copy of the same sequence. one copy of the repetition (hsp) and the independent clone (hcr) were sequenced by the sanger procedure (fig.). this sequence hybridized to four strains of t. cruzi tested and did not hybridize to eleven species of trypanosotids from five different genera, being a good candidate for diagnostic assays. genbank accession numbers: hsp#m31919, hcr#31920.
Genome Size, Karyotype Polymorphism and Chromosomal Evolution in Trypanosoma cruzi  [PDF]
Renata T. Souza, Fábio M. Lima, Roberto Moraes Barros, Danielle R. Cortez, Michele F. Santos, Esteban M. Cordero, Jeronimo Concei?ao Ruiz, Samuel Goldenberg, Marta M. G. Teixeira, José Franco da Silveira
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023042
Abstract: Background The Trypanosoma cruzi genome was sequenced from a hybrid strain (CL Brener). However, high allelic variation and the repetitive nature of the genome have prevented the complete linear sequence of chromosomes being determined. Determining the full complement of chromosomes and establishing syntenic groups will be important in defining the structure of T. cruzi chromosomes. A large amount of information is now available for T. cruzi and Trypanosoma brucei, providing the opportunity to compare and describe the overall patterns of chromosomal evolution in these parasites. Methodology/Principal Findings The genome sizes, repetitive DNA contents, and the numbers and sizes of chromosomes of nine strains of T. cruzi from four lineages (TcI, TcII, TcV and TcVI) were determined. The genome of the TcI group was statistically smaller than other lineages, with the exception of the TcI isolate Tc1161 (José-IMT). Satellite DNA content was correlated with genome size for all isolates, but this was not accompanied by simultaneous amplification of retrotransposons. Regardless of chromosomal polymorphism, large syntenic groups are conserved among T. cruzi lineages. Duplicated chromosome-sized regions were identified and could be retained as paralogous loci, increasing the dosage of several genes. By comparing T. cruzi and T. brucei chromosomes, homologous chromosomal regions in T. brucei were identified. Chromosomes Tb9 and Tb11 of T. brucei share regions of syntenic homology with three and six T. cruzi chromosomal bands, respectively. Conclusions Despite genome size variation and karyotype polymorphism, T. cruzi lineages exhibit conservation of chromosome structure. Several syntenic groups are conserved among all isolates analyzed in this study. The syntenic regions are larger than expected if rearrangements occur randomly, suggesting that they are conserved owing to positive selection. Mapping of the syntenic regions on T. cruzi chromosomal bands provides evidence for the occurrence of fusion and split events involving T. brucei and T. cruzi chromosomes.
Antibody isotype responses in Balb/c mice immunized with the cytoplasmic repetitive antigen and flagellar repetitive antigen of Trypanosoma cruzi
Pereira, Valéria RA;Lorena, Virginia Maria B;Ver?osa, Alinne Fernanda A;Silva, Edmilson D;Ferreira, Antonio GP;Montarroyos, Ulisses R;Silva, Ana P Galv?o;Gomes, Yara M;
Memórias do Instituto Oswaldo Cruz , 2003, DOI: 10.1590/S0074-02762003000600019
Abstract: in the present report we analyzed the levels of igg1, igg2a, igg2b and igg3 isotypes from balb/c mice immunized with cytoplasmic repetitive antigen (cra), and flagelar repetitive antigen (fra) of trypanosoma cruzi. the immunization was done by subcutaneous route three times (20 days apart) and the analysis was performed 14 days after each treatment. cra-immunized mice produced high levels of all igg isotypes, mainly igg3 and igg1. fra-immunization elicited only high levels of igg1.
Antibody isotype responses in Balb/c mice immunized with the cytoplasmic repetitive antigen and flagellar repetitive antigen of Trypanosoma cruzi  [cached]
Pereira Valéria RA,Lorena Virginia Maria B,Ver?osa Alinne Fernanda A,Silva Edmilson D
Memórias do Instituto Oswaldo Cruz , 2003,
Abstract: In the present report we analyzed the levels of IgG1, IgG2a, IgG2b and IgG3 isotypes from Balb/c mice immunized with cytoplasmic repetitive antigen (CRA), and flagelar repetitive antigen (FRA) of Trypanosoma cruzi. The immunization was done by subcutaneous route three times (20 days apart) and the analysis was performed 14 days after each treatment. CRA-immunized mice produced high levels of all IgG isotypes, mainly IgG3 and IgG1. FRA-immunization elicited only high levels of IgG1.
Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi
Marilyn Parsons, Elizabeth A Worthey, Pauline N Ward, Jeremy C Mottram
BMC Genomics , 2005, DOI: 10.1186/1471-2164-6-127
Abstract: Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs.Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been possible to ascribe function based solely on sequence similarity. Hence the connection of stimuli to protein phosphorylation networks remains enigmatic. The presence of numerous PKs with significant sequence similarity to known drug targets, as well as a large number of unusual kinases that might represent novel targets, strongly argue for functional analysis of these molecules.Trypanosomatid pathogens of humans include Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, causative agents of African sleeping sickness, Chagas disease, and cutaneous leishmaniasis respectively [1]. Trypanosoma brucei lives extracellularly in the human host, primarily in the bloodstream and cerebrospinal fluid. African sleeping sickness, which is estimated to afflict
Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole  [PDF]
Chiung-Kuang Chen,Siegfried S. F. Leung,Christophe Guilbert,Matthew P. Jacobson,James H. McKerrow,Larissa M. Podust
PLOS Neglected Tropical Diseases , 2010, DOI: 10.1371/journal.pntd.0000651
Abstract: Background Chagas Disease is the leading cause of heart failure in Latin America. Current drug therapy is limited by issues of both efficacy and severe side effects. Trypansoma cruzi, the protozoan agent of Chagas Disease, is closely related to two other major global pathogens, Leishmania spp., responsible for leishmaniasis, and Trypansoma brucei, the causative agent of African Sleeping Sickness. Both T. cruzi and Leishmania parasites have an essential requirement for ergosterol, and are thus vulnerable to inhibitors of sterol 14α-demethylase (CYP51), which catalyzes the conversion of lanosterol to ergosterol. Clinically employed anti-fungal azoles inhibit ergosterol biosynthesis in fungi, and specific azoles are also effective against both Trypanosoma and Leishmania parasites. However, modification of azoles to enhance efficacy and circumvent potential drug resistance has been problematic for both parasitic and fungal infections due to the lack of structural insights into drug binding. Methodology/Principal Findings We have determined the crystal structures for CYP51 from T. cruzi (resolutions of 2.35 ? and 2.27 ?), and from the related pathogen T. brucei (resolutions of 2.7 ? and 2.6 ?), co-crystallized with the antifungal drugs fluconazole and posaconazole. Remarkably, both drugs adopt multiple conformations when binding the target. The fluconazole 2,4-difluorophenyl ring flips 180° depending on the H-bonding interactions with the BC-loop. The terminus of the long functional tail group of posaconazole is bound loosely in the mouth of the hydrophobic substrate binding tunnel, suggesting that the major contribution of the tail to drug efficacy is for pharmacokinetics rather than in interactions with the target. Conclusions/Significance The structures provide new insights into binding of azoles to CYP51 and mechanisms of potential drug resistance. Our studies define in structural detail the CYP51 therapeutic target in T. cruzi, and offer a starting point for rationally designed anti-Chagasic drugs with improved efficacy and reduced toxicity.
Genome-wide in silico screen for CCCH-type zinc finger proteins of Trypanosoma brucei, Trypanosoma cruzi and Leishmania major
Susanne Kramer, Nicola C Kimblin, Mark Carrington
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-283
Abstract: We have identified the complete set of CCCH type zinc finger proteins in the available genomes of the kinetoplastid protozoa Trypanosoma brucei, Trypanosoma cruzi and Leishmania major. One fifths (20%) of all CCCH motifs fall into non-conventional classes and many had not been previously identified. One third of all CCCH proteins have more than one CCCH motif, suggesting multivalent RNA binding. One third have additional recognizable domains. The vast majority are unique to Kinetoplastida or to a subgroup within. Two exceptions are of interest: the putative orthologue of the mRNA nuclear export factor Mex67 and a 3'-5' exoribonuclease restricted to Leishmania species. CCCH motifs are absent from these proteins in other organisms and might be unique, novel features of the Kinetoplastida homologues. Of the others, several have a predicted, and in one case experimentally confirmed, connection to the ubiquitination pathways, for instance a HECT-type E3 ubiquitin ligase. The total number of kinetoplastid CCCH proteins is similar to the number in higher eukaryotes but lower than in yeast. A comparison of the genomic loci between the Trypanosomatidae homologues provides insight into both the evolution of the CCCH proteins as well as the CCCH motifs.This study provides the first systematic listing of the Kinetoplastida CCCH proteins. The number of CCCH proteins with more then one CCCH motif is larger than previously estimated, due to the identification of non-conventional CCCH motifs. Experimental approaches are now necessary to examine the functions of the many unique CCCH proteins as well as the function of the putative Mex67 and the Leishmania 3'-5' exoribonuclease.Pathogenic kinetoplastid protozoa, such as the widely studied 'Tritryps' Trypanosoma cruzi (Tc), Leishmania major (Lm) and Trypanosoma brucei (Tb), have complex biphasic life cycles and consequently require changes in gene expression in response to extrinsic and intrinsic signals. For instance, at least 5% of
Chromosome level assembly of the hybrid Trypanosoma cruzi genome
D Brent Weatherly, Courtney Boehlke, Rick L Tarleton
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-255
Abstract: Ultimately, 41 pairs of chromosomes were assembled using this approach, a number in agreement with the predicted number of T. cruzi chromosomes based upon pulse field gel analysis, with over 90% (21133 of 23216) of the genes annotated in the genome represented. The approach was substantiated through the use of Southern blot analysis to confirm the mapping of BAC clones using as probes the genes they are predicted to contain, and each chromosome construction was visually validated to ensure sufficient evidence was present to support the organization. While many members of large gene families are incorporated into the chromosome assemblies, the majority of genes excluded from the chromosomes belong to gene families, as these genes are frequently impossible to accurately position.Now assembled, these chromosomes bring T. cruzi to the same level of organization as its kinetoplastid relatives and have been used as the basis for the T. cruzi genome in TriTrypDB, a trypanosome database of EuPathDB. In addition, they will provide the foundation for analyses such as reverse genetics, where the location of genes and their alleles and/or paralogues is necessary and comparative genome hybridization analyses (CGH), where a chromosome-level view of the genome is ideal.The publication of the three trypanosomatid, or TriTryp, genomes in 2005 was an important advance in our understanding of the related parasites Trypanosoma cruzi, Leishmania major, and Trypanosoma brucei. However, as with other genomes [1,2] a published genome is not necessarily a completed genome. The issue of incompleteness within the TriTryp genomes is most striking with respect to T. cruzi which, because of its highly repetitive nature and the fact that the reference strain (CL Brener) is a hybrid oftwo distinct T. cruzi lineages, resulted in the publication of 32,746 contigs only partially assembled into 638 scaffolds with no complete chromosomes [3]. Though this resulted in a genome suitable for identifying an
Avalia??o hematológica e histopatológica de camundongos BALB/c e C57BL/6 expostos aos antígenos recombinantes Cytoplasmic Repetitive Antigen e Flagellar Repetitive Antigen de Trypanosoma cruzi
Pereira, Valéria Rêgo Alves;Lorena, Virginia Maria Barros de;Galv?o-da Silva, Ana Paula;Nakazawa, Mineo;Silva, Edimilson Domingos da;Ferreira, Antonio Gomes Pinto;Montarroyos, Ulisses;Coutinho, Eridan de Medeiros;Gomes, Yara de Miranda;
Revista da Sociedade Brasileira de Medicina Tropical , 2003, DOI: 10.1590/S0037-86822003000600016
Abstract: the cytoplasmic repetitive antigen and flagellar repetitive antigen recombinant antigens of trypanosoma cruzi were inoculated into balb/c and c57bl/6 mice and its effects evaluated at hematological and histopathological levels. the results showed that the histological pattern of the organs and the hematological profile of mice were not modified suggesting that these antigens are not harmful for the animal.
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