Avalia??o do efeito da inibi??o do reparo de s?tios ab?sicos na resposta inflamat?ria celular

Autor: Oliveira, Rayssa Karla de Medeiros
Jazyk: portugalština
Rok vydání: 2014
Předmět:
Zdroj: Repositório Institucional da UFRNUniversidade Federal do Rio Grande do NorteUFRN.
Druh dokumentu: masterThesis
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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES
Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Prote?nas do reparo por excis?o de bases (BER) t?m sido associadas a fun??es al?m do reparo e DNA. A apur?nica/apirimidinica endonuclease 1 (APE1) ? uma prote?na multifuncional envolvida em diversas atividades celulares como ativa??o redox de fatores de transcri??o, processamento de RNA e reparo de DNA. Alguns trabalhos t?m descrito a a??o da prote?na 8-oxoguanina (OGG1) na corre??o de les?es oxidadas no promotor como passo para a transcri??o de citocinas pro-inflamat?rias. Apesar de ser notadamente importante na ativa??o redox de fatores de transcri??o, como o fator nuclear ?B (NF- ?B) e AP-1, a atividade de reparo de APE1 ainda n?o foi associada ? resposta inflamat?ria. Neste trabalho, foram utilizadas an?lises bioinform?ticas e abordagens experimentais para investigar a rela??o entre a inibi??o do reparo de s?tios ab?sicos no DNA pela MX, mol?cula sint?tica inibidora indireta da atividade de reparo de APE1, e a modula??o de resposta inflamat?ria. Os resultados demonstraram que o tratamento de mon?citos com lipopolissacar?deo (LPS) e MX reduziu a express?o de citocinas, quimiocinas e receptores toll-like, e regulou negativamente processos biol?gicos da imunidade, como ativa??o de macr?fagos, e as vias ativadas pelo (NF-?B), fator de necrose tumoral (TNF-?) e interferon, sem induzir morte celular. A an?lise transcript?mica sugere que o tratamento LPS/MX induz disfun??es mitocondriais, estresse de ret?culo endoplasm?tico e ativa??o de vias de autofagia, provavelmente ativadas pelo comprometimento da energ?tica celular e/ou pelo ac?mulo de danos ao DNA, nuclear e mitocondrial. Adicionalmente, prop?e-se que a atividade de reparo de APE1 ? requerida para a transcri??o de genes inflamat?rios pela intera??o com s?tios ab?sicos no promotores espec?ficos e recrutamento de complexos transcricionais durante a sinaliza??o inflamat?ria. Este trabalho apresenta uma nova perspectiva acerca das intera??es entre a atividade do BER e a modula??o de resposta inflamat?ria, e sugere uma nova atividade para a prote?na APE1 como modular da resposta imune de maneira redox-independente.
Base excision repair (BER) proteins has been associated with functions beyond DNA repair. Apurynic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein involved in a plethora of cellular activities, such as redox activation of transcription factors, RNA processing and DNA repair. Some studies have described the action of the protein 8-oxoguanine (OGG1) in correcting oxidized lesions in promoters as a step in the transcription of pro-inflammatory cytokines. Despite being especially important in redox activation of transcription factors such as nuclear factor ?B (NF-?B) and AP- 1, the repair activity of APE1 has not yet been associated with the inflammatory response. In this study, experimental and bioinformatic analysis approaches have been used to investigate the relationship between inhibition of the repair of abasic sites in DNA by MX, a synthetic molecule designed to inhibt the repair activity of APE1, and the modulation of the inflammatory response. The results showed that treatment of monocytes with lipopolysaccharide (LPS) and MX reduced the expression of cytokines, chemokines and toll-like receptors, and negatively regulated biological immune processes, as macrophages activation, and NF-?B and tumor necrosis factor (TNF-?) and interferon pathways, without inducing cell death. The transcriptomic analysis suggests that LPS/MX treatment induces mitochondrial dysfunction, endoplasmic reticulum stress and activation of autophagy pathways, probably activated by impairment of cellular energy and/or the accumulation of nuclear and mitochondria DNA damage. Additionally, it is proposed that the repair activity of APE1 is required for transcription of inflammatory genes by interaction with abasic sites at specific promoters and recruitment of transcriptional complexes during inflammatory signaling. This work presents a new perspective on the interactions between the BER activity and the modulation of inflammatory response, and suggests a new activity for APE1 protein as modulator of the immune response in a redox-independent manner.
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