NEIL3 Gene

NEIL3 — Nei-Like DNA Glycosylase 3

Overview

NEIL3 (Nei-Like DNA Glycosylase 3) encodes a DNA repair enzyme that specializes in removing oxidized purine bases from DNA, particularly in proliferating cells and neural tissue.[@egiazarian2022] It plays critical roles in maintaining genomic integrity during neurogenesis and has been implicated in Alzheimer's disease, ALS, and various cancers.

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | NEIL3 |
| Full Name | Nei Like DNA Glycosylase 3 |
| Chromosomal Location | 4q34.3 |
| NCBI Gene ID | 55247 |
| OMIM ID | 608773 |
| Ensembl ID | ENSG00000128590 |
| UniProt ID | Q8TCJ1 |
| Encoded Protein | NEIL3 protein |
| Associated Diseases | Alzheimer's disease, ALS, cancer |

</div>

Introduction

NEIL3 — Nei-Like DNA Glycosylase 3

Overview

NEIL3 (Nei-Like DNA Glycosylase 3) encodes a DNA repair enzyme that specializes in removing oxidized purine bases from DNA, particularly in proliferating cells and neural tissue.[@egiazarian2022] It plays critical roles in maintaining genomic integrity during neurogenesis and has been implicated in Alzheimer's disease, ALS, and various cancers.

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | NEIL3 |
| Full Name | Nei Like DNA Glycosylase 3 |
| Chromosomal Location | 4q34.3 |
| NCBI Gene ID | 55247 |
| OMIM ID | 608773 |
| Ensembl ID | ENSG00000128590 |
| UniProt ID | Q8TCJ1 |
| Encoded Protein | NEIL3 protein |
| Associated Diseases | Alzheimer's disease, ALS, cancer |

</div>

Introduction

NEIL3 (Nei-Like DNA Glycosylase 3) is a DNA repair enzyme belonging to the FPG/Nei family of DNA glycosylases.[@kohler2018] Unlike other NEIL family proteins (NEIL1 and NEIL2), NEIL3 is primarily expressed in stem cells and neural tissue, where it plays crucial roles in maintaining genomic integrity during neurogenesis and other developmental processes.[@mccarroll2018]

The FPG/Nei family of DNA glycosylases is evolutionarily conserved and involved in the base excision repair (BER) pathway, specifically targeting oxidative DNA damage. NEIL3 has unique substrate specificity and expression patterns that distinguish it from its family members, making it particularly important in rapidly dividing cells and tissues with high metabolic activity.

Structure and Catalytic Mechanism

Protein Domain Architecture

NEIL3 is a 605-amino acid protein with several functional domains:

The catalytic mechanism involves:

• Base flipping: The enzyme inserts into the DNA helix and flips the damaged base out of the stack
• Glycosidic bond cleavage: Nucleophilic attack on the C1' carbon of the damaged base
• AP lyase activity: Strand incision at abasic sites generated by glycosylase activity

Substrate Specificity

NEIL3 recognizes and removes a unique set of oxidized purine bases:

• 8-oxoguanine (8-oxoG) — The most common oxidative DNA lesion
• Fapy-guanine (FapyG) — Oxidation product of guanine
• Spiroiminodihydantoin (Sp) — Secondary oxidation product
• Guanine hydrates — Less common oxidative lesions

Biological Functions

DNA Base Excision Repair

NEIL3 plays a central role in the base excision repair (BER) pathway:

Adult Neurogenesis

NEIL3 is essential for maintaining hippocampal neurogenesis:

• Neural stem cell proliferation — Supports continuous generation of new neurons in the subgranular zone
• DNA repair in progenitor cells — Protects rapidly dividing cells from mutagenic effects of oxidative damage
• Differentiation guidance — Influences lineage commitment of neural progenitor cells
• Pattern separation — NEIL3-dependent DNA repair enables proper hippocampal circuitry formation

Hypoxia-Ischemia Response

NEIL3 is upregulated following hypoxic-ischemic brain injury:

• Neuroprotection — Promotes neurogenesis after brain injury
• DNA damage repair — Removes oxidative lesions induced by ischemia
• Cell survival — Reduces apoptosis in neural tissue

Cancer Biology

NEIL3 has dual roles in cancer:

• Tumor suppression — In normal cells, NEIL3 protects against mutagenesis
• Tumor promotion — In some cancers, NEIL3 can support survival of transformed cells

Expression Patterns

Tissue Distribution

NEIL3 expression is highly tissue-specific:

• High expression — Neural stem cells, brain (hippocampus), spleen, testis
• Moderate expression — Bone marrow, intestinal crypts
• Low or absent — Most differentiated tissues

Cellular Localization

• Primary location — Nuclear
• Secondary location — Mitochondrial (in some cell types)

Disease Associations

Alzheimer's Disease

NEIL3 has emerged as an important player in Alzheimer's disease pathogenesis:

Amyloid Pathology

Egiazarian et al. (2022) conducted a comprehensive study showing age- and sex-dependent effects of NEIL3 on amyloid pathology:

• Female-specific effects — NEIL3 deficiency leads to decreased amyloid-β plaque deposition in female AD mice
• Male effects minimal — Male mice showed no significant difference in plaque load
• Mechanism unclear — Effects appear independent of DNA repair function

Neurogenesis Impairment

• Neural stem cell proliferation — NEIL3 deficiency reduces adult hippocampal neurogenesis
• Cognitive deficits — Loss of NEIL3 impairs working memory
• Age-dependent degeneration — Effects worsen with age

Genetic Associations

Torres et al. (2019) identified a NEIL3 promoter polymorphism associated with increased risk of Alzheimer's disease, providing genetic evidence for NEIL3's role in AD pathogenesis.

Tau Pathology

Recent research by Lewis et al. (2024) links NEIL3 to tauopathy progression:

• Tau phosphorylation — NEIL3 may influence tau metabolism
• NFT formation — Potential interaction with neurofibrillary tangle development
• TherapeuticTarget — NEIL3 modulation may slow disease progression

Amyotrophic Lateral Sclerosis (ALS)

NEIL3 mutations have been reported in some ALS cases:

• Motor neuron vulnerability — Motor neurons are particularly susceptible to oxidative damage
• Oxidative stress — ROS accumulation in ALS pathology
• DNA repair deficiency — Impaired NEIL3 function may contribute to motor neuron death

Brain Development Disorders

NEIL3 plays a role in proper brain development:

• Cortical development — Required for neuronal precursor proliferation
• Synaptogenesis — Affects synapse formation and function
• Cognitive development — Impacts learning and memory circuits

Cancer

NEIL3 has complex relationships with cancer:

• Neuroblastoma — High NEIL3 expression in some pediatric tumors
• glioma — May influence tumor progression
• Lymphoma — Altered expression in hematopoietic malignancies

Therapeutic Implications

Small Molecule Activators

Current research focuses on developing NEIL3-activating compounds:

• Enhance DNA repair — Increase NEIL3 activity to protect neurons
• Reduce oxidative damage — Support cellular defense mechanisms
• Neuroprotection — Potential for AD therapeutic development

Gene Therapy Approaches

• NEIL3 overexpression — Viral vector delivery to increase NEIL3 expression
• CRISPR activation — Epigenetic upregulation of endogenous NEIL3
• Cell therapy — NEIL3-expressing neural stem cells

Combination Therapies

NEIL3-targeted approaches may be combined with:

• Amyloid-targeting antibodies — Dual mechanism approaches
• Tau inhibitors — Comprehensive neuroprotection
• Antioxidants — Reduce oxidative stress substrate

Mouse Models

Neil3 Knockout Mice

Neil3-deficient mice exhibit:

• Viable and fertile — No embryonic lethality
• Reduced neurogenesis — Decreased hippocampal neural stem cells
• Age-dependent neurodegeneration — Progressive neuronal loss
• Cancer predisposition — Increased tumor formation

Conditional Knockouts

Brain-specific Neil3 deletion:

• Impaired neurogenesis — Severely reduced adult neurogenesis
• Cognitive deficits — Memory impairment
• DNA damage accumulation — Increased oxidative lesions

AD Model Crosses

Neil3 deficiency in APP/PS1 mice:

• Sex-dependent effects — Female-specific amyloid reduction
• Cognitive worsening — Impaired memory in both sexes
• Neurogenesis defects — Synergistic effects on neurogenesis

Interactions and Pathways

Protein Interactions

NEIL3 interacts with several DNA repair proteins:

• PARP1 — Poly(ADP-ribosylation) in damage response
• XRCC1 — Scaffold protein in BER
• Polβ — DNA polymerase in gap filling
• Ligase III — DNA ligation in BER

Signaling Pathways

NEIL3 is modulated by several pathways:

• p53 pathway — Transcriptional regulation
• ATM/ATR — Damage response signaling
• WNT signaling — Neurogenesis regulation
• FOXO transcription factors — Oxidative stress response

Epigenetic Regulation

NEIL3 affects epigenetic patterns:

• DNA methylation — Altered methylome in deficiency
• Histone modifications — Chromatin accessibility changes
• Gene expression — Dysregulated stress response genes

Cross-Links

• [DNA damage repair](/mechanisms/dna-damage-repair) — Pathway overview
• [Neurogenesis](/mechanisms/neurogenesis) — NEIL3 in brain development
• [Alzheimer's disease](/diseases/alzheimers-disease) — Associated disease
• [Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) — Associated disease
• [Oxidative stress](/mechanisms/oxidative-stress) — NEIL3 in oxidative damage
• [Base excision repair](/mechanisms/base-excision-repair) — Specific pathway
• [DNA glycosylases](/proteins/dna-glycosylases) — Protein family
• [Hippocampus](/cell-types/neurons#hippocampal-neurons) — Regional expression

Key Publications

See Also

• [Genes](/genes) — Gene directory
• [DNA repair mechanisms](/mechanisms/dna-damage-repair) — Related pathways
• [Neurodegenerative diseases](/diseases) — Disease overview
• [DNA glycosylases](/proteins) — Related protein families

References