Functional polymorphisms in Nrf2: implications for human disease
Introduction
Nrf2 is a ubiquitous transcription factor essential in host defense [1], [2]. Nrf2 transcriptionally activates ARE-bearing genes in response to reactive oxygen species (ROS) produced during oxidative stress [3], [4], [5], [6]. Nrf2 homeostasis is regulated by Kelch-like erythroid-derived Cap’n’Collar Homology (ECH)-associated protein 1 (Keap1), a cytoplasmic Nrf2 suppressor [7]. In unstressed conditions, Keap1 binds Nrf2 and brings it into close proximity with Cullin 3 (CUL3), an E3 ligase which polyubiquinates Nrf2 for proteasomal degradation [8]. However, electrophilic and oxidative insults are known to modify thiol residues in Keap1, which may alter binding interactions between Keap1, CUL3, and Nrf2, and permit newly synthesized Nrf2 to bypass Keap1 inhibition and transactivate antioxidant target genes [9]. It is important to note that there exist other Keap1-independent modes of Nrf2 regulation, including GSK3/betaTrCP-dependent degradation through the Neh6 domain [10]. Greater detail about the regulation of Nrf2 is presented elsewhere in the series of papers for this Special Issue of Free Radical Biology & Medicine.
Mice with targeted deletion of Nrf2 (Nrf2-/-) have been widely used to investigate the role of the transcription factor in disease models during the last decade [11], [12], [13]. Moreover, murine Nrf2 was identified through positional cloning as a susceptibility gene in oxidative lung disorders [14], [15.]. Animal studies have focused on the Nrf2-ARE pathway as a means to identify novel therapeutic targets for human diseases in which oxidative stress is implicated, and translational research efforts have confirmed the importance of Nrf2 in oxidative disease pathogenesis and cancer progression.
The current review addresses genetic and somatic mutations in human Nrf2. We identified and categorized genetic variations including single nucleotide polymorphisms (SNPs) and haplotypes available from the 1000 Genomes Project and the International HapMap Project databases. We have also annotated putative functional genetic polymorphisms reported to associate with disease risk. Finally, we report somatic mutations identified through targeted cohort and whole exome sequencing of tumor cell/tissue samples from neoplastic individuals.
Section snippets
Nrf2 gene and protein domains
Human Nrf2 is located in the cytogenetic band 2q31.2 of chromosome 2 spanning 177230303 - 177265131 bp (gene ID: 4780) on the reverse strand as a complementary sequence (Fig. 1). Nrf2 mRNA is 2,859 base pairs long (variant 1: NM_006164) and the full-length transcript encodes a protein containing 605 amino acid (aa) residues (isoform 1: NP_006155 or Q16236). Transcript variants have been reported [10]; variant 2 (NM_001145412, 2746 bp) has an alternate promoter, 5’UTR and downstream start codon.
Polymorphisms and haplotype alleles
Genome-wide association studies (GWAS) have examined SNPs across the genome to identify ‘risk’ genotypes significantly more prevalent in an affected group for disease association. Supporting GWAS, the 1000 Genomes Project has sequenced more than 2000 genomes (~2500 to date) of individuals with diverse ethnicity. The HapMap Project has also mapped combinations of alleles at specific loci (haplotypes) to generate DNA sequence variation patterns that contribute to disease risk. In conjunction with
Somatic Nrf2 mutations
Recent research has provided significant insight into mutagenesis and cancer development in various organs such as the lung. Somatic or acquired mutations change the genetic structure of diploid cells but are not heritable. Together with epigenetic changes (epimutations), somatic mutations predispose individuals to cancer through changes in the activity of affected genes. Six patterns of somatic mutations, C>A/G>T, C>G/G>C, C>T/G>A, T>A/A>T, T>C/A>G, and T>G/A>C, have been established in the
Conclusions
Studies using mice with targeted deletion of Nrf2 have yielded valuable insight to the role of this transcription factor in health and disease in multiple organ systems, and potential understanding of factors that contribute to human diseases. Subsequent investigations that have characterized the genetic and molecular function of human Nrf2, including associations of Nrf2 SNPs with disease phenotypes, have also provided novel targets for disease prevention. A limitation of the association
Conflict of Interests
The authors declare that there are no conflicts of interest.
Acknowledgments
The research related to the manuscript was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS). Drs. Michael Fessler and Donald Cook at the NIEHS provided excellent critical review of the manuscript.
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Emerging roles of Keap1/Nrf2 signaling in the thyroid gland and perspectives for bench-to-bedside translation
2022, Free Radical Biology and MedicineCitation Excerpt :The NFE2L2 promoter harbors three functional single-nucleotide polymorphisms (SNPs) that impact the promoter's transcriptional activity. These SNPs have been associated with various diseases whose pathogenesis involves oxidative stress [37–40]. We have previously described a genetic interaction between the NFE2L2 promoter genotype and a functional SNP in the promoter of SELENOS [41].
Counteracting health risks by Modulating Homeostatic Signaling
2022, Pharmacological ResearchInflammatory potential of diet and aging
2022, Diet, Inflammation, and HealthReal-ambient exposure to air pollution exaggerates excessive growth of adipose tissue modulated by Nrf2 signal
2020, Science of the Total EnvironmentCitation Excerpt :Compelling evidences supported the association between genetic variation of Nrf2 and disease risk to human (Marzec et al., 2007; Scutt et al., 2019; Yang et al., 2019). Nrf2 was highly polymorphic and mutagenic in human, which mostly influenced the expression of Nrf2 (Cho et al., 2015). Among the diseasome map, Nrf2 was found to be correlated with various metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity (Jimenez-Osorio et al., 2016; Uruno et al., 2015; Vasileva et al., 2020; Umapathy et al., 2019).
Molecular mechanisms and systemic targeting of NRF2 dysregulation in cancer
2020, Biochemical PharmacologyCitation Excerpt :The exact functions of NRF2 isoforms are not characterized yet. In addition, single nucleotide polymorphisms (SNPs) in the human Nrf2 locus were identified in various chronic diseases and most of them are located in the 5′-flanking regions and introns [63]. Whether and how are they associated with susceptibility to these diseases are unclear.