DNA topoisomerase 3α is involved in homologous recombination repair and replication stress response in Trypanosoma cruzi

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dc.contributor(LCC) Laboratório de Ciclo Celularpt_BR
dc.contributor.authorCosta-Silva, Héllida Marinapt_BR
dc.contributor.authorResende, Bruno Carvalhopt_BR
dc.contributor.authorUmaki, Adriana Castilhos Souzapt_BR
dc.contributor.authorPrado, Willianpt_BR
dc.contributor.authorSilva, Marcelo Santos dapt_BR
dc.contributor.authorVirgílio, Stelapt_BR
dc.contributor.authorMacedo, Andrea Marapt_BR
dc.contributor.authorPena, Sérgio Danilo Junhopt_BR
dc.contributor.authorTahara, Erich Birellipt_BR
dc.contributor.authorTosi, Luiz Ricardo Orsinipt_BR
dc.contributor.authorElias, Maria Carolinapt_BR
dc.contributor.authorAndrade, Luciana Oliveirapt_BR
dc.contributor.authorReis-Cunha, João Luíspt_BR
dc.contributor.authorFranco, Glória Reginapt_BR
dc.contributor.authorFragoso, Stenio Perdigãopt_BR
dc.contributor.authorMachado, Carlos Renatopt_BR
dc.date.accessioned2021-06-04T17:40:56Z-
dc.date.available2021-06-04T17:40:56Z-
dc.date.issued2021pt_BR
dc.identifier.citationCosta-Silva HM, Resende BC, Umaki ACS, Prado W, Silva MS, Virgílio S, et al. DNA topoisomerase 3α is involved in homologous recombination repair and replication stress response in Trypanosoma cruzi. Front. Cell Dev. Biol.. 2021 May;9:633195w. doi:10.3389/fcell.2021.633195.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/3817-
dc.description.abstractDNA 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.pt_BR
dc.description.sponsorship(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.description.sponsorship(CAPES) Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorpt_BR
dc.description.sponsorship(FAPEMIG) Fundação de Amparo à Pesquisa do Estado de Minas Geraispt_BR
dc.description.sponsorship(FIOCRUZ) Fundação Oswaldo Cruzpt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.format.extent633195wpt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofFrontiers in Cell and Developmental Biologypt_BR
dc.rightsOpen accesspt_BR
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/pt_BR
dc.titleDNA topoisomerase 3α is involved in homologous recombination repair and replication stress response in Trypanosoma cruzipt_BR
dc.typeArticlept_BR
dc.rights.licenseCC BYpt_BR
dc.identifier.doi10.3389/fcell.2021.633195pt_BR
dc.identifier.urlhttps://doi.org/10.3389/fcell.2021.633195pt_BR
dc.contributor.external(UFMG) Universidade Federal de Minas Geraispt_BR
dc.contributor.externalInstituto Carlos Chagas (ICC). Fundação Oswaldo Cruz (FioCruz)pt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.identifier.citationvolume9pt_BR
dc.subject.keywordDNA topoisomerase 3αpt_BR
dc.subject.keywordhomologous recombinationpt_BR
dc.subject.keywordreplication stresspt_BR
dc.subject.keywordTrypanosoma cruzipt_BR
dc.subject.keywordDNA damagept_BR
dc.subject.keywordDNA repairpt_BR
dc.subject.keyworddormancypt_BR
dc.relation.ispartofabbreviatedFront. Cell Dev. Biol.pt_BR
dc.identifier.citationabntv. 9, 633195w, maio. 2021pt_BR
dc.identifier.citationvancouver2021 May;9:633195wpt_BR
dc.contributor.butantanSilva, Marcelo Santos da|:Aluno|:LCC - Laboratório de Ciclo Celular:Centro de Toxinas, Resposta-imune e Sinalização Celular (CeTICS)pt_BR
dc.contributor.butantanElias, Maria Carolina|:Pesquisador|:LCC - Laboratório de Ciclo Celular:Centro de Toxinas, Resposta-imune e Sinalização Celular (CeTICS)pt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico¦¦pt_BR
dc.sponsorship.butantan(CAPES) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior¦¦pt_BR
dc.sponsorship.butantan(FAPEMIG) Fundação de Amparo à Pesquisa do Estado de Minas Gerais¦¦pt_BR
dc.sponsorship.butantanFundação Oswaldo Cruz¦¦pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2013/07467-1pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2014/24170-5pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2016/50050-2pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2018/14398-0pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
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