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Functional characterization of 8-oxoguanine DNA glycosylase of Trypanosoma cruzi

Furtado, C and Kunrath-Lima, M and Rajão, MA and Mendes, IC and de Moura, MB and Campos, PC and Macedo, AM and Franco, GR and Pena, SDJ and Teixeira, SMR and van Houten, B and Machado, CR (2012) Functional characterization of 8-oxoguanine DNA glycosylase of Trypanosoma cruzi. PLoS ONE, 7 (8).

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Abstract

The oxidative lesion 8-oxoguanine (8-oxoG) is removed during base excision repair by the 8-oxoguanine DNA glycosylase 1 (Ogg1). This lesion can erroneously pair with adenine, and the excision of this damaged base by Ogg1 enables the insertion of a guanine and prevents DNA mutation. In this report, we identified and characterized Ogg1 from the protozoan parasite Trypanosoma cruzi (TcOgg1), the causative agent of Chagas disease. Like most living organisms, T. cruzi is susceptible to oxidative stress, hence DNA repair is essential for its survival and improvement of infection. We verified that the TcOGG1 gene encodes an 8-oxoG DNA glycosylase by complementing an Ogg1-defective Saccharomyces cerevisiae strain. Heterologous expression of TcOGG1 reestablished the mutation frequency of the yeast mutant ogg1-/- (CD138) to wild type levels. We also demonstrate that the overexpression of TcOGG1 increases T. cruzi sensitivity to hydrogen peroxide (H2O2). Analysis of DNA lesions using quantitative PCR suggests that the increased susceptibility to H2O2 of TcOGG1-overexpressor could be a consequence of uncoupled BER in abasic sites and/or strand breaks generated after TcOgg1 removes 8-oxoG, which are not rapidly repaired by the subsequent BER enzymes. This hypothesis is supported by the observation that TcOGG1-overexpressors have reduced levels of 8-oxoG both in the nucleus and in the parasite mitochondrion. The localization of TcOgg1 was examined in parasite transfected with a TcOgg1-GFP fusion, which confirmed that this enzyme is in both organelles. Taken together, our data indicate that T. cruzi has a functional Ogg1 ortholog that participates in nuclear and mitochondrial BER. © 2012 Furtado et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Furtado, C
Kunrath-Lima, M
Rajão, MA
Mendes, IC
de Moura, MB
Campos, PC
Macedo, AM
Franco, GR
Pena, SDJ
Teixeira, SMR
van Houten, Bbev15@pitt.eduBEV15
Machado, CR
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorKorolev, SergeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Hillman Cancer Center
Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 2 August 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0042484
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Other ID: NLM PMC3411635
PubMed Central ID: PMC3411635
PubMed ID: 22876325
Date Deposited: 18 Oct 2012 16:47
Last Modified: 02 Feb 2019 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/15880

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