Banca de QUALIFICAÇÃO: THAIS TEIXEIRA OLIVEIRA

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : THAIS TEIXEIRA OLIVEIRA
DATE: 03/12/2019
TIME: 14:00
LOCAL: Sala Carl Peter von Dietrich - Departamento de Bioquímica
TITLE:

Analysis of the effect of base excision repair inhibition on transcription regulation during inflammation

KEY WORDS:

DNA repair. Inflammation. NRF1. ELK1. Mitochondrial biogenesis. Ribosomal biogenesis.

PAGES: 84
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:

APE1 / Ref-1 is a mammalian protein formed by two functional domains. The N-terminal domain, which is capable of reduce transcription factors like NF-kB, AP-1 and HIF-1 and increase their DNA binding capabilities and the expression of target genes. The c-terminal domain responsible for endonuclease activity that makes APE1 / Ref-1 the major endonuclease of the base excision repair pathway. Recently, it has been shown that the presence of 8-oxoG in promoters of some genes is actually an inducer of expression in the presence of OGG1 and APE1/ Ref-1. Thus, APE1 / Ref-1 also regulates gene expression depending on its repair function. Due to its various functions, APE1 is a potential therapeutic target that has been studied mainly in cancer. However, the role of each APE1 function in transcriptional regulation is not yet fully understood and proteins capable of interacting with APE1 are discovered each year. In a previous study by our group, it was observed that inhibition of APE1 / Ref-1 endonuclease activity by methoxyamine decreases the expression of proinflammatory cytokines and chemokines in LPS pretreated monocytes. In order to observe which other genes have their expression affected by inhibition of AP site repair, as well as identify possible APE1 / Ref-1 regulators and partners in this response RNA-Seq was performed from LPS-treated monocytes (24h) and methoxyamine (4h), and the differentially expressed genes after methoxyamine treatment were analyzed for their functions and possible expression regulators. In addition, these genes were compared with those differentially expressed after E3330 treatment under the same conditions. The main regulators of the networks as well as their targets were analyzed for their expression by q-PCR and Western blot. With this data, we conclude that inhibition of AP site repair during inflammation decreases cell cycle progression-related gene expression and increases mTOR inhibition-related gene expression, suggesting that the cell is signaling for a growth stop. In addition, we observed that the repair function is capable of regulating the transcription of mitochondrial biogenesis-related genes, as well as the expression of the 47S pre-rRNA without affecting the processing of this RNA. Finally, methoxyamine was able to dramatically c-Myc expression, which makes this inhibitor an even more promising therapeutic potential.

BANKING MEMBERS:
Presidente - 1837354 - JULLIANE TAMARA ARAUJO DE MELO CAMPOS
Externa ao Programa - 1251018 - RIVA DE PAULA OLIVEIRA
Interna - 1199127 - SILVIA REGINA BATISTUZZO DE MEDEIROS