Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRN |
Texto Completo: | https://repositorio.ufrn.br/handle/123456789/45094 |
Resumo: | The 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 transcription |
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Oliveira, Thais TeixeiraFontes-Dantas, Fabrícia LimaOliveira, Rayssa Karla de MedeirosPinheiro, Daniele Maria LopesCoutinho, Leonam GomesSilva, Vandeclecio Lira daSouza, Sandro José deAgnez-Lima, Lucymara Fassarella2021-11-30T14:12:43Z2021-11-30T14:12:43Z2021OLIVEIRA, 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.2021.731588https://repositorio.ufrn.br/handle/123456789/4509410.3389/fcell.2021.731588FrontiersAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessApurinic/apyrimidinic endonuclease I (APE1)DNA repairTranscriptional controlInflammationETS transcription factorChemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanismsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleThe 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 transcriptionengreponame:Repositório Institucional da UFRNinstname:Universidade Federal do Rio Grande do Norte (UFRN)instacron:UFRNLICENSElicense.txtlicense.txttext/plain; charset=utf-81484https://repositorio.ufrn.br/bitstream/123456789/45094/3/license.txte9597aa2854d128fd968be5edc8a28d9MD53ORIGINALChemicalInhibitionApurinic-Apyrimidinic_Oliveira_2021.pdfChemicalInhibitionApurinic-Apyrimidinic_Oliveira_2021.pdfapplication/pdf11125640https://repositorio.ufrn.br/bitstream/123456789/45094/1/ChemicalInhibitionApurinic-Apyrimidinic_Oliveira_2021.pdf7fb46dee4ebe26ca38bff9ef0dcb3c3dMD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufrn.br/bitstream/123456789/45094/2/license_rdfe39d27027a6cc9cb039ad269a5db8e34MD52123456789/450942021-11-30 11:12:43.476oai:https://repositorio.ufrn.br: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Repositório de PublicaçõesPUBhttp://repositorio.ufrn.br/oai/opendoar:2021-11-30T14:12:43Repositório Institucional da UFRN - Universidade Federal do Rio Grande do Norte (UFRN)false |
dc.title.pt_BR.fl_str_mv |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
title |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
spellingShingle |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms Oliveira, Thais Teixeira Apurinic/apyrimidinic endonuclease I (APE1) DNA repair Transcriptional control Inflammation ETS transcription factor |
title_short |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
title_full |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
title_fullStr |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
title_full_unstemmed |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
title_sort |
Chemical inhibition of Apurinic-apyrimidinic endonuclease 1 Redox and DNA repair functions affects the inflammatory response via different but overlapping mechanisms |
author |
Oliveira, Thais Teixeira |
author_facet |
Oliveira, 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 |
author_role |
author |
author2 |
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 |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Oliveira, 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 |
dc.subject.por.fl_str_mv |
Apurinic/apyrimidinic endonuclease I (APE1) DNA repair Transcriptional control Inflammation ETS transcription factor |
topic |
Apurinic/apyrimidinic endonuclease I (APE1) DNA repair Transcriptional control Inflammation ETS transcription factor |
description |
The 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 transcription |
publishDate |
2021 |
dc.date.accessioned.fl_str_mv |
2021-11-30T14:12:43Z |
dc.date.available.fl_str_mv |
2021-11-30T14:12:43Z |
dc.date.issued.fl_str_mv |
2021 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
OLIVEIRA, 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.2021.731588 |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufrn.br/handle/123456789/45094 |
dc.identifier.doi.none.fl_str_mv |
10.3389/fcell.2021.731588 |
identifier_str_mv |
OLIVEIRA, 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.2021.731588 10.3389/fcell.2021.731588 |
url |
https://repositorio.ufrn.br/handle/123456789/45094 |
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eng |
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eng |
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