Human NEIL3 Gene Expression Regulated by Epigenetic-Like Oxidative DNA Modification

Area of Science:

• Genomics
• DNA Repair
• Epigenetics

Background:

• Oxidative and inflammatory stress induce NEIL3 gene expression.
• Oxidation of guanine (G) to 8-oxo-7,8-dihydroguanine (OG) occurs during stress.
• A G-rich promoter element in NEIL3 is a potential G-quadruplex-forming sequence (PQS).

Purpose of the Study:

• To investigate the role of the NEIL3 PQS in gene regulation during oxidative stress.
• To explore the mechanism of NEIL3 activation involving OG formation and repair.
• To determine if the NEIL3 PQS acts as a redox-sensitive regulatory element.

Main Methods:

• In vitro studies using thermodynamic and chemical analyses.
• Cellulo studies to examine DNA repair processes.
• Bioinformatic analysis of mammalian genomes for sequence conservation.

Main Results:

• OG formation in the NEIL3 PQS triggers base excision repair by OGG1, creating an abasic site (AP).
• The AP site destabilizes DNA, promoting a G-quadruplex (G4) fold within the PQS.
• APE1 poorly cleaves the AP site in the G4 context, allowing it to act as a transcriptional transactivator.

Conclusions:

• The NEIL3 PQS functions as a redox switch, regulating NEIL3 expression via OG modification.
• This mechanism allows cells to respond to mutagenic DNA damage during oxidative stress.
• Conserved NEIL3 PQS across mammalian genomes suggests evolutionary selection for this regulatory pathway.