Bifunctional Glycosylase NEIL2 Plays an Important Role in Maintaining Cellular Genomic Integrity

Abstract

Over 70,000 DNA lesions occur in the cell every day, and the inability to properly repair them can lead to mutations and destabilize the genome, resulting in carcinogenesis. The base excision repair (BER) pathway is critical for maintaining genomic integrity by repairing small base lesions, abasic sites, and single-stranded breaks. The Nei-like 2 (NEIL2) enzyme is a critical bifunctional DNA glycosylase in BER that preferentially excises abasic sites from single-stranded, double-stranded, and bubble-structured DNA. NEIL2 is both structurally and functionally dynamic. It undergoes a large conformational change when bound to a DNA substrate and is involved in various molecular pathways including the canonical BER, BER associated with transcription, epigenetic regulation, and immune regulation, converging on its role as an AP lyase. Several germline and somatic variants of NEIL2 with altered expression and enzymatic activity have been reported in the literature linking them to cancers. The G230W somatic variant has defective glycosylase and lyase activities. Functional studies performed on G230W-expressing MCF10A reveal induction of anchorage-independent growth, AP site accumulation, genomic instability, and altered cell cycle progression. High-throughput drug screen performed on G230W-expressing MCF7 reveals several intriguing candidates that could affect therapeutic response. Preliminary validation assays suggest a mild sensitivity of G230W-expressing cells to olaparib and cabozantinib. Furthermore, additional MCF10A cell lines with the expression of germline variants R103Q and R203Q were also generated, providing avenues for future exciting studies into NEIL2 cellular functions.