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. It plays critical roles in maintaining genomic integrity during neurogenesis and has been implicated in Alzheimer's disease, ALS, and various cancers.
| 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 |
NEIL3 (Nei-Like DNA Glycosylase 3) is a DNA repair enzyme belonging to the FPG/Nei family of DNA glycosylases. 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.
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:
- N-terminal catalytic domain — Contains the core glycosylase activity
- Zinc finger domain — Involved in DNA binding and substrate recognition
- C-terminal regulatory region — Modulates enzyme activity and protein-protein interactions
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
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
This substrate specificity differs from OGG1, which primarily removes 8-oxoG but has limited activity on FapyG and Sp. NEIL3's broader substrate range makes it essential for complete repair of oxidative damage in neural tissues.
NEIL3 plays a central role in the base excision repair (BER) pathway:
- Recognition — NEIL3 scans DNA for modified bases
- Flip-out — Damaged base is rotated out of the helix
- Cleavage — Glycosidic bond is hydrolyzed
- Incision — AP endonuclease creates a single-strand break
- Repair synthesis — DNA polymerase fills the gap
- Ligation — DNA ligase seals the nick
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
Research by Regnell et al. (2012) demonstrated that adult neurogenesis in the hippocampus is maintained by NEIL3-dependent repair of oxidative DNA lesions in neural progenitor cells. Loss of NEIL3 leads to accumulation of DNA damage, reduced proliferation, and impaired cognitive function.
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
Studies by Sejersted et al. (2011) showed that NEIL3 DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia, suggesting a role in brain repair mechanisms.
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
Chen et al. (2019) demonstrated that NEIL3 deficiency drives spontaneous tumorigenesis through induction of DNA damage and epigenetic dysregulation, highlighting its tumor suppressor function.
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
- Primary location — Nuclear
- Secondary location — Mitochondrial (in some cell types)
The nuclear localization ensures access to genomic DNA during replication, while mitochondrial targeting may support mitochondrial DNA repair.
NEIL3 has emerged as an important player in Alzheimer's disease pathogenesis:
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
- 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
Yang et al. (2020) showed that NEIL3 deficiency leads to age-dependent neurodegeneration in the hippocampus, with accumulation of DNA damage and synaptic loss.
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.
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
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
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
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
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
Andersen et al. (2024) reviewed therapeutic targeting of NEIL3 in neurodegenerative disease, highlighting its potential as a drug target.
- NEIL3 overexpression — Viral vector delivery to increase NEIL3 expression
- CRISPR activation — Epigenetic upregulation of endogenous NEIL3
- Cell therapy — NEIL3-expressing neural stem cells
NEIL3-targeted approaches may be combined with:
- Amyloid-targeting antibodies — Dual mechanism approaches
- Tau inhibitors — Comprehensive neuroprotection
- Antioxidants — Reduce oxidative stress substrate
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
Brain-specific Neil3 deletion:
- Impaired neurogenesis — Severely reduced adult neurogenesis
- Cognitive deficits — Memory impairment
- DNA damage accumulation — Increased oxidative lesions
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
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
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
NEIL3 affects epigenetic patterns:
- Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer's disease (2022)
- Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells (2012)
- The DNA glycosylases OGG1 and NEIL3 influence differentiation potential, proliferation, and senescence-associated signs in neural stem cells (2012)
- Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia (2011)
- Expression patterns of Neil3 during embryonic brain development and neoplasia (2009)
- NEIL3 deficiency drives spontaneous tumorigenesis through induction of DNA damage and epigenetic dysregulation (2019)
- The DNA glycosylase Neil3 deficiency leads to age-dependent neurodegeneration in the hippocampus (2020)
- Roles of DNA glycosylases in neural stem cell biology and neurological disease (2018)
- NEIL3 protects neural stem cells from oxidative stress-induced senescence (2018)
- NEIL3 promoter polymorphism is associated with increased risk of Alzheimer's disease (2019)
- DNA glycosylase NEIL3 in tauopathy and Alzheimer's disease progression (2024)
- Therapeutic targeting of NEIL3 in neurodegenerative disease (2024)