Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms

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dc.contributor.authorOliveira, Thais Teixeira
dc.contributor.authorFontes-Dantas, Fabrícia Lima
dc.contributor.authorOliveira, Rayssa Karla de Medeiros
dc.contributor.authorPinheiro, Daniele Maria Lopes
dc.contributor.authorCoutinho, Leonam Gomes
dc.contributor.authorSilva, Vandeclecio Lira da
dc.contributor.authorSouza, Sandro José de
dc.contributor.authorAgnez-Lima, Lucymara Fassarella
dc.date.accessioned2021-11-30T14:12:43Z
dc.date.available2021-11-30T14:12:43Z
dc.date.issued2021
dc.description.resumoThe presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcriptionpt_BR
dc.identifier.citationOLIVEIRA, Thais Teixeira; FONTES-DANTAS, Fabrícia Lima; OLIVEIRA, Rayssa Karla de Medeiros; PINHEIRO, Daniele Maria Lopes; COUTINHO, Leonam Gomes; SILVA, Vandeclecio Lira da; SOUZA, Sandro José de; AGNEZ-LIMA, Lucymara Fassarella. Chemical Inhibition of Apurinic-Apyrimidinic Endonuclease 1 Redox and DNA Repair Functions Affects the Inflammatory Response via Different but Overlapping Mechanisms. Frontiers in Cell and Developmental Biology, [S. l.], v. 9, p. 1-17, set. 2021. DOI: https://doi.org/10.3389/fcell.2021.731588pt_BR
dc.identifier.doi10.3389/fcell.2021.731588
dc.identifier.urihttps://repositorio.ufrn.br/handle/123456789/45094
dc.languageenpt_BR
dc.publisherFrontierspt_BR
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Brazil*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/br/*
dc.subjectApurinic/apyrimidinic endonuclease I (APE1)pt_BR
dc.subjectDNA repairpt_BR
dc.subjectTranscriptional controlpt_BR
dc.subjectInflammationpt_BR
dc.subjectETS transcription factorpt_BR
dc.titleChemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanismspt_BR
dc.typearticlept_BR

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