NEIL2 is a bifunctional DNA glycosylase that plays a critical role in base excision repair (BER) by recognizing and excising oxidized DNA lesions, particularly cytosine oxidation products and abasic sites from various DNA structures including single-stranded, double-stranded, and bubble-structured DNA 1. The enzyme initiates BER by cleaving N-glycosidic bonds and introducing strand breaks with both 3'- and 5'-phosphate termini through beta-delta elimination 1. Beyond genome maintenance, NEIL2 functions in active DNA demethylation, immune response modulation, and mitochondrial genome protection 2. NEIL2 activity is dynamically regulated through post-translational modifications: phosphorylation by PKC reduces enzymatic activity while CDK5 phosphorylation operates through distinct regulatory mechanisms, with oxidative stress triggering rapid dephosphorylation 3. Acetylation at Lys49 by p300 inactivates both base excision and AP lyase activities, providing reversible regulation 4. Clinically, NEIL2 variants and polymorphisms (rs804270, rs8191664) associate with altered cancer susceptibility and radiotherapy response in rectal and cervical cancers, with reduced NEIL2 expression correlating with increased malignancy risk 5 6. NEIL2 loss causes accumulation of oxidized lesions and neurodevelopmental defects, emphasizing its multifunctional importance in cellular homeostasis.