The DNA damage response is developmentally regulated in the African trypanosome

Vieira-da-Rocha, João Pedro; Passos‐Silva, Danielle Gomes; Mendes, Isolda C.; Rocha, Elizângela Almeida; Gomes, Dawidson Assis; Machado, Carlos Renato; McCulloch, Richard

doi:10.1016/j.dnarep.2018.11.005

Cited by 9 publications

(10 citation statements)

References 85 publications

(129 reference statements)

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“…In procyclic form T. brucei, the rate of HR-mediated DSB repair after ionizing radiation (IR) is considerably faster than that observed here for benznidazole: γH2A formation and TbRAD51 deposition peaked approximately 2 and 2 to 5 hr post-IR damage, respectively (Marin et al, 2018). The variation in recruitment kinetics shown by the HR factors in DSB repair may reflect differences between the two T. brucei developmental stages examined, as observed for other lesions (Vieira-da-Rocha et al, 2019) or the nature of the DSB-inducing treatment itself.…”

Section: Discussionmentioning

confidence: 59%

Unraveling the antitrypanosomal mechanism of benznidazole and related 2‐nitroimidazoles: From prodrug activation to DNA damage

Dattani

Drammeh

Mahmood

et al. 2021

Molecular Microbiology

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Protozoan parasites belonging to the genus Trypanosoma are responsible for a series of medically and veterinary important infections. In humans, Trypanosoma cruzi and Trypanosoma brucei are the etiological agents of Chagas disease and human African trypanosomiasis (HAT), respectively, while animal African trypanosomiasis is caused by several species including T. brucei, T. congolense, and T. vivax. The burden associated with these insect transmitted infections has had a major impact on the public health and socio-economic development of many poor rural communities in Latin America and sub-Saharan Africa, effectively trapping sufferers and their families in a disease/

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Section: Discussionmentioning

confidence: 59%

Unraveling the antitrypanosomal mechanism of benznidazole and related 2‐nitroimidazoles: From prodrug activation to DNA damage

Dattani

Drammeh

Mahmood

et al. 2021

Molecular Microbiology

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“…However, in trypanosomatids, no specific DNA glycosylase capable of removing N-methyl purines has so far been identified ( Charret et al, 2012 ). Recently, it was shown that MMS-induced lesions are repaired by NER and homologous recombination in T. brucei ( Vieira-da-Rocha et al, 2018 ). In T. cruzi , Rad51 single knockout parasites were sensitive to treatment with 1.5 mM MMS.…”

Section: Discussionmentioning

confidence: 99%

DNA Topoisomerase 3α Is Involved in Homologous Recombination Repair and Replication Stress Response in Trypanosoma cruzi

Costa-Silva

Resende

Umaki

et al. 2021

Front. Cell Dev. Biol.

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DNA topoisomerases are enzymes that modulate DNA topology. Among them, topoisomerase 3α is engaged in genomic maintenance acting in DNA replication termination, sister chromatid separation, and dissolution of recombination intermediates. To evaluate the role of this enzyme in Trypanosoma cruzi, the etiologic agent of Chagas disease, a topoisomerase 3α knockout parasite (TcTopo3α KO) was generated, and the parasite growth, as well as its response to several DNA damage agents, were evaluated. There was no growth alteration caused by the TcTopo3α knockout in epimastigote forms, but a higher dormancy rate was observed. TcTopo3α KO trypomastigote forms displayed reduced invasion rates in LLC-MK2 cells when compared with the wild-type lineage. Amastigote proliferation was also compromised in the TcTopo3α KO, and a higher number of dormant cells was observed. Additionally, TcTopo3α KO epimastigotes were not able to recover cell growth after gamma radiation exposure, suggesting the involvement of topoisomerase 3α in homologous recombination. These parasites were also sensitive to drugs that generate replication stress, such as cisplatin (Cis), hydroxyurea (HU), and methyl methanesulfonate (MMS). In response to HU and Cis treatments, TcTopo3α KO parasites showed a slower cell growth and was not able to efficiently repair the DNA damage induced by these genotoxic agents. The cell growth phenotype observed after MMS treatment was similar to that observed after gamma radiation, although there were fewer dormant cells after MMS exposure. TcTopo3α KO parasites showed a population with sub-G1 DNA content and strong γH2A signal 48 h after MMS treatment. So, it is possible that DNA-damaged cell proliferation due to the absence of TcTopo3α leads to cell death. Whole genome sequencing of MMS-treated parasites showed a significant reduction in the content of the multigene families DFG-1 and RHS, and also a possible erosion of the sub-telomeric region from chromosome 22, relative to non-treated knockout parasites. Southern blot experiments suggest telomere shortening, which could indicate genomic instability in TcTopo3α KO cells owing to MMS treatment. Thus, topoisomerase 3α is important for homologous recombination repair and replication stress in T. cruzi, even though all the pathways in which this enzyme participates during the replication stress response remains elusive.

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“…The repair of UV lesions may also be associated with the recombination process. In T. brucei , it was seen that cells deficient in the Rad51 gene are not able to adequately repair lesions caused by methyl methanesulfonate (MMS) 49 , 71 , 72 .…”

Section: Discussionmentioning

confidence: 99%

“…This parasite contains DNA glycosylases that participate in the kDNA damage response 43 , 44 , as well as polymerases involved in the response to oxidative stress, such as Polβ, Polβ-PAK 46 , 47 and Polκ, which are able to interact with intermediates of the homologous recombination 48 . Studies in T. brucei showed that the bloodstream form is able to deal with damage caused by cisplatin, hydrogen peroxide and methylmethanesulfonate (MMS), suggesting that DNA repair pathways are present in the parasite mitochondrion and that TbRad51 might be crucial to the response to alkylation lesions 49 .…”

Section: Introductionmentioning

confidence: 99%

Importance of Angomonas deanei KAP4 for kDNA arrangement, cell division and maintenance of the host-bacterium relationship

Gonçalves¹,

Catta-Preta²,

Repolês³

et al. 2021

Sci Rep

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Angomonas deanei coevolves in a mutualistic relationship with a symbiotic bacterium that divides in synchronicity with other host cell structures. Trypanosomatid mitochondrial DNA is contained in the kinetoplast and is composed of thousands of interlocked DNA circles (kDNA). The arrangement of kDNA is related to the presence of histone-like proteins, known as KAPs (kinetoplast-associated proteins), that neutralize the negatively charged kDNA, thereby affecting the activity of mitochondrial enzymes involved in replication, transcription and repair. In this study, CRISPR-Cas9 was used to delete both alleles of the A. deanei KAP4 gene. Gene-deficient mutants exhibited high compaction of the kDNA network and displayed atypical phenotypes, such as the appearance of a filamentous symbionts, cells containing two nuclei and one kinetoplast, and division blocks. Treatment with cisplatin and UV showed that Δkap4 null mutants were not more sensitive to DNA damage and repair than wild-type cells. Notably, lesions caused by these genotoxic agents in the mitochondrial DNA could be repaired, suggesting that the kDNA in the kinetoplast of trypanosomatids has unique repair mechanisms. Taken together, our data indicate that although KAP4 is not an essential protein, it plays important roles in kDNA arrangement and replication, as well as in the maintenance of symbiosis.

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The DNA damage response is developmentally regulated in the African trypanosome

Cited by 9 publications

References 85 publications

Unraveling the antitrypanosomal mechanism of benznidazole and related 2‐nitroimidazoles: From prodrug activation to DNA damage

Unraveling the antitrypanosomal mechanism of benznidazole and related 2‐nitroimidazoles: From prodrug activation to DNA damage

DNA Topoisomerase 3α Is Involved in Homologous Recombination Repair and Replication Stress Response in Trypanosoma cruzi

Importance of Angomonas deanei KAP4 for kDNA arrangement, cell division and maintenance of the host-bacterium relationship

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