NEIL2, short for Nei-like 2, is a critical bifunctional DNA glycosylase. It plays a central role in the base excision repair (BER) pathway, which is crucial for maintaining genome integrity by eliminating oxidized DNA base lesions [3]. NEIL2 preferentially excises cytosine oxidation products and abasic sites from different DNA structures, and is also involved in multiple cellular processes such as genome maintenance, modulation of the immune response, and active DNA demethylation [1,3].

Neil2-null mice show an age-dependent accumulation of oxidative DNA damage, mainly in the transcribed regions of the genome, along with increased inflammatory responsiveness [6,7]. In SARS-CoV-2 infection, lower NEIL2 levels are observed in severely infected patients. Neil2-null mice infected with a mouse-adapted CoV-2 strain suffer more severe viral infection with increased proinflammatory gene expression and higher mortality. Recombinant NEIL2 delivered into permissive cells decreases viral replication, as NEIL2 binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis [2,5]. Also, intrapulmonary administration of purified NEIL2 abrogates NF-κB-mediated inflammation by blocking NF-κB's binding to target gene promoters [4].

In conclusion, NEIL2 is essential for maintaining genome integrity, especially in transcriptionally active sequences, and modulating the immune response. Studies using Neil2-null mouse models have revealed its significance in combating viral infections like SARS-CoV-2 and in controlling inflammation-related diseases. Understanding NEIL2 provides insights into disease mechanisms and potential therapeutic strategies for diseases associated with genomic instability and inflammation [1-5,7,10].