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Previous issue date: 2014-08-21 / 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.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/19978 |
| Date | 21 August 2014 |
| Creators | Oliveira, Rayssa Karla de Medeiros |
| Contributors | 00297997750, http://lattes.cnpq.br/1083882171718362, Vieira, Leda Quercia, 40867056649, http://lattes.cnpq.br/6809125371733700, Pedrosa, Matheus de Freitas Fernandes, 96728647449, http://lattes.cnpq.br/2929963416385218, Agnez, Lucymara Fassarella |
| Publisher | Universidade Federal do Rio Grande do Norte, PROGRAMA DE P?S-GRADUA??O EM BIOQU?MICA, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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