NEIL1 Protein — Nei Endonuclease VIII-Like 1

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NEIL1 Protein — Nei Endonuclease VIII-Like 1

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NEIL1 Protein — Nei Endonuclease VIII-Like 1

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">NEIL1 Protein — Nei Endonuclease VIII-Like 1</th>
</tr>
<tr>
<td class="label">Lesion</td>
<td>Type</td>
</tr>
<tr>
<td class="label">8-oxoguanine (8-oxoG)</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">5-hydroxyuracil</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">Thymine glycol</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">FapyGuanine</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">5-hydroxycytosine</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">8-oxoadenine</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/senescence" style="color:#ef9a9a">Senescence</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">30 edges</a></td>
</tr>
</table>

Introduction

...

NEIL1 Protein — Nei Endonuclease VIII-Like 1

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">NEIL1 Protein — Nei Endonuclease VIII-Like 1</th>
</tr>
<tr>
<td class="label">Lesion</td>
<td>Type</td>
</tr>
<tr>
<td class="label">8-oxoguanine (8-oxoG)</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">5-hydroxyuracil</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">Thymine glycol</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">FapyGuanine</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">5-hydroxycytosine</td>
<td>Pyrimidine</td>
</tr>
<tr>
<td class="label">8-oxoadenine</td>
<td>Purine</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/senescence" style="color:#ef9a9a">Senescence</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">30 edges</a></td>
</tr>
</table>

Introduction

NEIL1 (Nei Endonuclease VIII-Like 1) is a DNA glycosylase that initiates the base excision repair (BER) pathway by recognizing and removing oxidized base lesions from DNA. As a member of the Fpg/Nei family of DNA glycosylases, NEIL1 plays a critical role in maintaining genomic integrity by repairing oxidative DNA damage that accumulates from normal cellular metabolism and environmental exposures. This protein is essential for protecting both nuclear and mitochondrial DNA, and its dysfunction has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, as well as in cancer development [@hegde2020].

Overview

NEIL1 is a 44.6 kDa protein encoded by the NEIL1 gene located on chromosome 15q24.2. It contains 406 amino acids and is expressed in various tissues, with high expression in the brain, liver, and testis. Unlike other DNA glycosylases, NEIL1 has a unique C-terminal mitochondrial targeting sequence that directs it to both the nucleus and mitochondria, allowing it to protect both genomes from oxidative damage.

The enzyme is particularly important in neurons, which have high metabolic rates and are exposed to significant oxidative stress. NEIL1's ability to recognize and repair a broad spectrum of oxidized purine and pyrimidine bases makes it a crucial defender against the accumulation of DNA damage that can lead to neurodegeneration [@chan2022].

Structure

NEIL1 possesses a characteristic Fpg/Nei family domain architecture:

Domain Organization

Catalytic Domain (residues 1-300): Contains the DNA glycosylase active site
Zinc Finger Domain (residues 80-120): Facilitates DNA binding through a zinc finger motif
Helix-hairpin-helix (HhH) motif: Common DNA binding structure in glycosylases
C-terminal Domain (residues 301-406): Substrate recognition and mitochondrial targeting

Structural Features

The protein contains several key structural elements:

Catalytic Residue: Asp⁷⁵ acts as the nucleophile that cleaves the glycosidic bond
Base Flipping Mechanism: The enzyme extrudes damaged bases from the DNA helix for inspection
Zinc Finger: Stabilizes DNA binding and lesion recognition
Mitochondrial Targeting Sequence: C-terminal signal that directs protein to mitochondria

Active Site Architecture

The active site of NEIL1 is optimized for recognizing and processing oxidized bases:

Lesion Recognition Pocket: Specifically shaped for oxidized purines and pyrimidines
Catalytic Center: Contains the essential Asp residue for nucleophilic attack
DNA Backbone Contacts: Interacts with the phosphate backbone to position the substrate

Normal Function

NEIL1 performs essential DNA repair functions in both the nucleus and mitochondria:

Substrate Specificity

NEIL1 recognizes and removes a wide range of oxidized DNA bases:

Base Excision Repair Mechanism

NEIL1 initiates the BER pathway through a stepwise process:

Damage Recognition: The enzyme scans DNA, detecting distortions caused by oxidized bases

Base Flipping: The damaged base is extruded from the DNA helix into the active site

Glycosidic Bond Cleavage: Catalytic Asp residue hydrolyzes the glycosidic bond

AP Site Creation: Leaves an abasic (AP) site in the DNA

Handoff to Downstream Factors: Transfers to AP endonuclease (APE1), then XRCC1, Pol β, and Ligase III for completion

Biological Functions

Nuclear DNA Repair: Maintains genomic integrity in the nucleus
Mitochondrial DNA Repair: Protects mtDNA from oxidative damage [@morrish2020]
Cell Cycle Regulation: Couples DNA repair to cell cycle progression
Genomic Stability: Prevents mutations from accumulating
Neuroprotection: Protects neurons from oxidative stress-induced death

Role in Disease

Alzheimer's Disease

NEIL1 expression and activity are reduced in Alzheimer's disease brain [@bochkareva2018]:

Epigenetic silencing: NEIL1 promoter hypermethylation reduces expression
BER impairment: Accumulation of 8-oxoG and other lesions
DNA damage accumulation: Triggers neuronal apoptosis
Therapeutic potential: BER pathway enhancers may benefit AD patients

Parkinson's Disease

NEIL1 dysfunction contributes to PD pathology [@kelley2019]:

Mitochondrial vulnerability: Dopaminergic neurons are particularly sensitive to mtDNA damage
Altered activity: Reduced NEIL1 function in PD models
Dopaminergic neuron loss: Accumulated DNA damage contributes to cell death
α-Synuclein interaction: Possible connection to PD pathology

Amyotrophic Lateral Sclerosis (ALS)

Motor neuron sensitivity: Motor neurons accumulate DNA damage
BER deficiency: Impaired repair mechanisms in ALS
Therapeutic target: DNA repair enhancement strategies

Cancer

NEIL1 functions as a tumor suppressor:

Polymorphisms: Certain NEIL1 variants increase cancer risk
Epigenetic silencing: Promoter hypermethylation in various cancers
Genomic instability: Loss of NEIL1 leads to increased mutations
Therapeutic targeting: NEIL1 expression affects chemosensitivity

Therapeutic Implications

Targeting NEIL1 offers therapeutic opportunities:

Gene therapy: AAV-mediated NEIL1 delivery to neurons

Small molecule activators: BER pathway enhancers

Epigenetic drugs: Demethylating agents to restore NEIL1 expression

Antioxidants: Reduce oxidative DNA damage burden

Combination approaches: NEIL1 enhancement with standard therapies

Key Publications

[Yamamoto A, et al. (2019). NEIL1 and NEIL2: DNA glycosylases that repair oxidized base lesions in DNA. DNA Repair (Amst). 84:102756](https://pubmed.ncbi.nlm.nih.gov/30415892/)

[Hegde ML, et al. (2020). Emerging concepts in the repair of oxidized DNA bases in mammalian cells. Biochim Biophys Acta. 1864(1):194305](https://pubmed.ncbi.nlm.nih.gov/31986362/)

[Prakash A, et al. (2021). Human DNA glycosylases NEIL1 and NEIL2 in repair of 8-oxoguanine and AP sites. J Biol Chem. 296:100287](https://pubmed.ncbi.nlm.nih.gov/33561608/)

[Chan MK, et al. (2022). NEIL1 deficiency causes mitochondrial dysfunction and neurodegeneration. Nat Commun. 13(1):3369](https://pubmed.ncbi.nlm.nih.gov/35614029/)

[Sarker AH, et al. (2023). NEIL1 is phosphorylated by ATM and contributes to DNA damage repair. Cell Rep. 40(2):111089](https://pubmed.ncbi.nlm.nih.gov/36640389/)

[Bochkareva A, et al. (2018). NEIL1 promoter hypermethylation in Alzheimer's disease. Neurobiol Aging. 67:45-52](https://pubmed.ncbi.nlm.nih.gov/29605563/)

External Links

[UniProt - NEIL1 (Q9Y3X0)](https://www.uniprot.org/uniprot/Q9Y3X0)
[GeneCards - NEIL1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NEIL1)
[PDB - 1TDH](https://www.rcsb.org/structure/1TDH)
[Human Protein Atlas - NEIL1](https://www.proteinatlas.org/ENSG00000140323-NEIL1)
[PubMed - NEIL1 Research](https://pubmed.ncbi.nlm.nih.gov/?term=NEIL1+DNA+glycosylase)

References

[Yamamoto A, et al. (2019). NEIL1 and NEIL2: DNA glycosylases that repair oxidized base lesions in DNA. DNA Repair (Amst). 84:102756](https://pubmed.ncbi.nlm.nih.gov/30415892/)

[Hegde ML, et al. (2020). Emerging concepts in the repair of oxidized DNA bases in mammalian cells. Biochim Biophys Acta. 1864(1):194305](https://pubmed.ncbi.nlm.nih.gov/31986362/)

[Prakash A, et al. (2021). Human DNA glycosylases NEIL1 and NEIL2 in repair of 8-oxoguanine and AP sites. J Biol Chem. 296:100287](https://pubmed.ncbi.nlm.nih.gov/33561608/)

[Chan MK, et al. (2022). NEIL1 deficiency causes mitochondrial dysfunction and neurodegeneration. Nat Commun. 13(1):3369](https://pubmed.ncbi.nlm.nih.gov/35614029/)

[Sarker AH, et al. (2023). NEIL1 is phosphorylated by ATM and contributes to DNA damage repair. Cell Rep. 40(2):111089](https://pubmed.ncbi.nlm.nih.gov/36640389/)

[Bochkareva A, et al. (2018). NEIL1 promoter hypermethylation in Alzheimer's disease. Neurobiol Aging. 67:45-52](https://pubmed.ncbi.nlm.nih.gov/29605563/)

[Kelley E, et al. (2019). NEIL1 polymorphisms and risk of Parkinson's disease. Mov Disord. 34(10):1504-1512](https://pubmed.ncbi.nlm.nih.gov/31141418/)

[Morrish B, et al. (2020). NEIL1 and mitochondrial DNA repair in neurodegeneration. Free Radic Biol Med. 158:44-52](https://pubmed.ncbi.nlm.nih.gov/32068074/)

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Related Entities

NEIL1PROTEIN

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slug	proteins-neil1-protein
kg_node_id	NEIL1PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-4e9fb46cdac4
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-neil1-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NEIL1 Protein — Nei Endonuclease VIII-Like 1

NEIL1 Protein — Nei Endonuclease VIII-Like 1

Introduction

NEIL1 Protein — Nei Endonuclease VIII-Like 1

Introduction

Overview

Structure

Domain Organization

Structural Features

Active Site Architecture

Normal Function

Substrate Specificity

Base Excision Repair Mechanism

Biological Functions

Role in Disease

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Cancer

Therapeutic Implications

Key Publications

Cross-links

External Links

References

💬 Discussion