Role of NEIL1 in genome maintenance

Abstract

Phylogenetic analyses of DNA glycosylases that function in the initiation step of base excision repair reveal a high degree of conservation within the genes encoding Nei-like DNA glycosylase 1 (NEIL1). In concert with other glycosylases, this enzyme is an important player in cleansing both nuclear and mitochondrial genomes of a wide variety of damaged DNA bases. The relative efficiency of NEIL1 to catalyze release of ring-opened formamido-pyrimidines (Fapy) and alkylated-Fapy adducts, multiple ring-saturated pyrimidines, secondary oxidation products of 8-oxoguanine, and psoralen-derived crosslinks is augmented by pre-mRNA editing at codon 242, resulting in cells containing both NEIL1-Lys242 and edited Arg242. The biological significance of NEIL1 was revealed through investigations of mutagenesis and carcinogenesis in murine models, primarily using aflatoxin B₁ (AFB₁) as a genotoxicant challenge, which forms stable AFB₁-FapyGua adducts. Specifically, Neil1 knockout mice were > 3-fold more susceptible to AFB₁-induced carcinogenesis as compared to either wild-type or nucleotide excision repair-deficient Xpa^-/- mice. These data are well-supported by duplex sequencing analyses that showed increased AFB₁-induced mutagenesis in Neil1^-/- mice relative to wild-type or Xpa^-/- mice. Given the biological impact of Neil1 deficiencies in cancer, metabolic syndrome, and neurodegeneration, extrapolation to humans carrying single nucleotide polymorphisms (SNPs) in NEIL1 may suggest that deleterious variants could increase disease risk following various genotoxicant exposures. To address this hypothesis, we have undertaken a systematic characterization of human NEIL1 SNP variants that are distributed throughout the world. The goal of this review is to provide comprehensive analyses of the biochemistry and biology of NEIL1.