Role of NEIL1 in genome maintenance

Published

February 19, 2025

Author(s)

Amanda McCullough, Irina Minko, Michael Luzadder, Jamie Zuckerman, Pawel Jaruga, Vladimir Vartanian, M Miral Dizdar, R. Stephen Lloyd

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 as a genotoxicant challenge, which forms stable AFB1-FapyGua adducts (AFB1 - aflatoxin B1). Specifically, mice knocked out for Neil1 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 control or NER (nucleotide excision repair) -deficient mice. Given the biological impact of Neil1 deficiencies in cancer, metabolic syndrome, and neurodegeneration, extrapolation to humans carrying single nucleotide polymorphisms 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 single nuclear polymorphism (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.

Citation

Dna Repair

Pub Type

Journals

Download Paper

https://doi.org/10.1016/j.dnarep.2025.103820

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Keywords

NEIL1, single nucleotide polymorphism, genome maintenance, oxidative DNA damage, DNA repair, BER, NER, cancer biomarkers

Citation

McCullough, A. , Minko, I. , Luzadder, M. , Zuckerman, J. , Jaruga, P. , Vartanian, V. , Dizdar, M. and Lloyd, R. (2025), Role of NEIL1 in genome maintenance, Dna Repair, [online], https://doi.org/10.1016/j.dnarep.2025.103820, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=959099 (Accessed April 30, 2025)