UNG Gene

UNG Gene

Introduction

Uracil-DNA glycosylase (UNG) is a critical DNA repair enzyme that protects the genome from uracil incorporation and deamination. The UNG gene encodes the primary enzyme responsible for removing uracil residues from DNA, initiating the base excision repair (BER) pathway. This page covers the gene structure, protein function, and its specific roles in [neurodegenerative diseases](/diseases/alzheimers-disease) including [Alzheimer's Disease](/diseases/alzheimers-disease) and [Parkinson's Disease](/diseases/parkinsons-disease).

{{- start}} [@pearl2000]

{{- infobox [@kavli2002]
| name = UNG [@nilsen2000]
| image = [@poulin1999]
| caption = UNG DNA repair enzyme [@visnes2009]
| gene_symbol = UNG [@mullins2019]
| gene_name = Uracil-DNA glycosylase [@yang2001]
| chromosome = 12
| locus = 12q24.1
| ncbi_gene_id = 7306
| omim_id = 191525
| ensembl_id = ENSG00000166200
| uniprot_id = P13051
| encoded_protein = UNG Protein
}}

Overview

...

UNG Gene

Introduction

Uracil-DNA glycosylase (UNG) is a critical DNA repair enzyme that protects the genome from uracil incorporation and deamination. The UNG gene encodes the primary enzyme responsible for removing uracil residues from DNA, initiating the base excision repair (BER) pathway. This page covers the gene structure, protein function, and its specific roles in [neurodegenerative diseases](/diseases/alzheimers-disease) including [Alzheimer's Disease](/diseases/alzheimers-disease) and [Parkinson's Disease](/diseases/parkinsons-disease).

{{- start}} [@pearl2000]

{{- infobox [@kavli2002]
| name = UNG [@nilsen2000]
| image = [@poulin1999]
| caption = UNG DNA repair enzyme [@visnes2009]
| gene_symbol = UNG [@mullins2019]
| gene_name = Uracil-DNA glycosylase [@yang2001]
| chromosome = 12
| locus = 12q24.1
| ncbi_gene_id = 7306
| omim_id = 191525
| ensembl_id = ENSG00000166200
| uniprot_id = P13051
| encoded_protein = UNG Protein
}}

Overview

The UNG gene (Uracil-DNA glycosylase) encodes a DNA repair enzyme that removes uracil residues from DNA. This gene is crucial for maintaining genome integrity through the base excision repair (BER) pathway. UNG deficiency has been implicated in neurodegenerative diseases due to accumulated DNA damage. The enzyme acts as a front-line defense against the most common form of DNA damage—uracil incorporation—and its activity is essential for preventing mutations that can lead to cellular dysfunction and death. [@krokan2013]

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th>Symbol</th><td>UNG</td></tr>
<tr><th>Full Name</th><td>Uracil-DNA Glycosylase</td></tr>
<tr><th>Chromosomal Location</th><td>12q24.1</td></tr>
<tr><th>NCBI Gene ID</th><td>[7306](https://www.ncbi.nlm.nih.gov/gene/7306)</td></tr>
<tr><th>OMIM</th><td>[191525](https://www.omim.org/entry/191525)</td></tr>
<tr><th>Ensembl</th><td>ENSG00000166200</td></tr>
<tr><th>UniProt</th><td>[P13051](https://www.uniprot.org/uniprot/P13051)</td></tr>
<tr><th>Gene Family</th><td>Uracil-DNA glycosylase family, DNA glycosylase superfamily I</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/stroke" style="color:#ef9a9a">Stroke</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
</tr>
</table>
</div>

Protein Structure and Function

Enzyme Classification

UNG belongs to the family of DNA glycosylases, enzymes that recognize and remove damaged bases from DNA. Specifically, it is a uracil-DNA glycosylase that catalyzes the hydrolysis of the N-glycosidic bond between the uracil base and the deoxyribose sugar, releasing free uracil and creating an abasic site (AP site) in the DNA backbone. This reaction initiates the base excision repair (BER) pathway. [@krokan2013]

Structural Features

The UNG protein contains several key structural elements:

N-terminal domain: Contains the catalytic residues and DNA-binding interface

Active site: Conserved motifs involved in uracil recognition and catalytic activity

DNA-binding groove: Shaped to accommodate both single-stranded and double-stranded DNA

Lesion recognition loop: Flexible region that scans DNA for uracil residues

The crystal structure of UNG reveals a base-flipping mechanism where the uracil base rotates out of the DNA helix into the enzyme's active site, enabling catalytic cleavage. This mechanism is conserved across uracil-DNA glycosylases from bacteria to humans. [@pearl2000]

Catalytic Mechanism

UNG catalyzes the removal of uracil through a base-catalyzed hydrolysis reaction:

Uracil recognition: The enzyme scans DNA and detects uracil by hydrogen bonding patterns that differ from normal bases

Base flipping: The uracil base rotates out of the helix into the active site

Glycosidic bond cleavage: Nucleophilic attack by a water molecule, activated by a catalytic cysteine residue

AP site creation: The resulting abasic site is handed off to AP endonuclease (APE1) for subsequent processing

Substrate Specificity

UNG efficiently removes:

• Deaminated cytosine (U): The most common substrate, arising from spontaneous cytosine deamination to uracil
• Incorporated uracil: dUTP misincorporated during DNA replication
• Uracil in various sequence contexts: Active on single-stranded and double-stranded DNA

Role in Base Excision Repair

The BER Pathway

The base excision repair (BER) pathway is the primary mechanism for repairing small, non-helix-distorting DNA lesions. UNG initiates this pathway as the damage-specific enzyme that recognizes and removes uracil. The complete BER process involves: [@krokan2013]

Damage recognition: UNG identifies uracil in DNA

Base removal: UNG cleaves the N-glycosidic bond, releasing uracil

AP site processing: AP endonuclease (APE1) cleaves the phosphodiester backbone 5' to the AP site

DNA strand scission: DNA polymerase β removes the deoxyribose phosphate

DNA synthesis: DNA polymerase β fills in the correct nucleotide

DNA ligation: DNA ligase seals the nick

Mitochondrial vs Nuclear UNG

UNG function extends to both nuclear and mitochondrial DNA compartments:

• Nuclear UNG: Maintains genomic integrity during replication and transcription
• Mitochondrial UNG (UNG2): Variant isoform with mitochondrial targeting sequence, crucial for repairing mitochondrial DNA (mtDNA) that is particularly vulnerable to oxidative damage [@canugovi2020]

The mitochondrial isoform is essential for preventing mtDNA mutation accumulation, which is especially relevant in energy-demanding tissues like the brain.

Back-up Glycosylases

When UNG activity is reduced, backup DNA glycosylases can partially compensate:

• SMUG1: Single-strand-selective monofunctional uracil-DNA glycosylase
• TDG: Thymine-DNA glycosylase, removes uracil and other base lesions
• MBD4: Methyl-CpG binding domain protein 4

These enzymes provide redundancy in uracil removal but have different substrate preferences and tissue distributions. [@ahnesorg2006]

Expression Pattern

Tissue Distribution

UNG exhibits broad tissue expression with notable patterns: [@kavli2018]

• High expression: Lymphoid tissues (spleen, thymus, bone marrow), testis, gastrointestinal tract
• Moderate expression: Liver, kidney, lung, brain
• Cell-type specific: Higher activity in proliferating cells

In the brain, UNG is expressed in:

• [Neurons](/entities/neurons) - particularly vulnerable cell types
• [Microglia](/cell-types/microglia) - immune cells in the CNS
• [Astrocytes](/cell-types/astrocytes) - support cells
• [Oligodendrocytes](/cell-types/oligodendrocytes) - myelin-producing cells

Brain Region Expression

UNG expression in the brain varies by region:

• Cerebral cortex: Moderate expression in pyramidal neurons
• Hippocampus: High expression in CA1-CA3 regions and dentate gyrus
• Cerebellum: Purkinje cells show distinctive UNG activity
• Substantia nigra: Dopaminergic neurons express UNG, relevant to [Parkinson's Disease](/diseases/parkinsons-disease)
• Basal ganglia: Variable expression patterns

Disease Associations

Alzheimer's Disease

UNG plays a significant role in [Alzheimer's Disease](/diseases/alzheimers-disease) pathogenesis through multiple mechanisms: [@parikh2015][@scalfaro2022]

DNA damage accumulation: Impaired UNG activity leads to increased uracil accumulation in neuronal DNA

Oxidative stress: Amyloid-beta ([Aβ](/proteins/amyloid-beta)) and [tau](/proteins/tau-protein) pathology generate oxidative stress that overwhelms DNA repair capacity

Neuronal vulnerability: Post-mitotic neurons cannot dilute DNA damage through cell division, making efficient repair essential

Epigenetic alterations: UNG deficiency may affect DNA methylation patterns through altered dUTP/dTTP ratios

Mitochondrial dysfunction: Reduced UNG activity in mitochondria contributes to mtDNA mutation accumulation

Evidence from studies:

• Reduced UNG activity in AD brain tissue
• Elevated uracil levels in AD neuronal DNA
• Correlation between DNA repair capacity and cognitive decline

Parkinson's Disease

UNG dysfunction contributes to [Parkinson's Disease](/diseases/parkinsons-disease) through: [@canugovi2020][@bjorklund2019]

Mitochondrial DNA damage: Dopaminergic neurons are particularly vulnerable to mtDNA damage due to high oxidative stress

Impaired BER capacity: Age-related decline in UNG activity accelerates neuronal loss

Alpha-synuclein interaction: [Alpha-synuclein](/proteins/alpha-synuclein) aggregation may impair DNA repair machinery including UNG

Environmental toxins: MPTP and other PD-inducing toxins generate oxidative DNA damage that overwhelms repair systems

Key mechanisms:

• Reduced UNG expression in substantia nigra neurons
• Accumulation of mtDNA mutations in PD patients
• Correlation between DNA repair capacity and disease progression

Aging and Cognitive Decline

UNG function declines with age: [@moreira2022]

• Decreased UNG expression and activity in aged brain
• Accumulation of uracil in genomic and mitochondrial DNA
• Reduced capacity for DNA repair in neurons
• Contributes to age-related cognitive decline and neurodegeneration

Cancer Risk

UNG mutations or deficiency increase cancer susceptibility: [@scharma2021]

• Hyper-IgM syndrome: UNG deficiency in humans leads to immunodeficiency with increased cancer risk
• Lymphomas and leukemias: Accumulated mutations drive malignant transformation
• Solid tumors: Various carcinomas show UNG dysregulation

Interaction Network

UNG interacts with multiple proteins in the DNA repair machinery:

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| APE1 | Direct binding | AP site processing in BER |
| DNA Polymerase β | Direct binding | Gap-filling DNA synthesis |
| XRCC1 | Direct binding | Scaffold protein in BER |
| DNA Ligase III | Direct binding | Nick sealing |
| PNKP | Direct binding | 5'-phosphate processing |
| SMUG1 | Functional redundancy | Backup uracil removal |

Therapeutic Implications

Enhancing DNA Repair Capacity

Strategies to improve UNG function in neurodegeneration: [@norbury2020]

Gene therapy: Viral vector delivery of UNG to neurons

Small molecule activators: Compounds that enhance UNG activity

Substrate analogs: dUTPase inhibitors to reduce uracil incorporation

Combination Approaches

• Antioxidant therapy: Reduce oxidative DNA damage burden
• DNA repair enhancement: Combine UNG modulation with other BER components
• Mitochondrial targeting: Mitochondria-specific UNG delivery

Challenges

• BBB penetration: Achieving therapeutic concentrations in the brain
• Selectivity: Avoiding effects on rapidly dividing cells
• Timing: Intervention likely needs to occur early in disease course

Cross-Linking

Related Proteins

• [UNG Protein](/proteins/ung-protein) - Protein product
• [APE1](/genes/ape1) - AP endonuclease 1, next step in BER
• [PARP1](/genes/parp1) - Poly(ADP-ribose) polymerase 1, DNA damage sensor
• [XRCC1](/genes/xrcc1) - DNA repair scaffold protein

Related Mechanisms

• [Base Excision Repair](/mechanisms/base-excision-repair) - Primary repair pathway
• [DNA Repair](/mechanisms/dna-repair-pathway) - Overview of DNA repair
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-parkinsons) - Energy failure in PD
• [Oxidative Stress](/mechanisms/oxidative-stress) - DNA damage source

Related Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Aging-Related Neurodegeneration](/mechanisms/brain-aging)

See Also

• [DNA Repair](/mechanisms/dna-repair-pathway)
• [Base Excision Repair](/mechanisms/base-excision-repair)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [UNG Protein](/proteins/ung-protein)

References

[Krokan HE, et al. (2002). DNA glycosylases in the base excision repair pathway. Progress in Nucleic Acid Research and Molecular Biology, 72, 89-126.](https://pubmed.ncbi.nlm.nih.gov/12471710/) [@krokan2002]

[Pearl LH. (2000). Structure and function in the uracil-DNA glycosylase superfamily. Cell Death & Differentiation, 7(10), 1151-1164.](https://pubmed.ncbi.nlm.nih.gov/10932255/) [@pearl2000]

[Kavli B, et al. (2002). Uracil-DNA glycosylases. DNA Repair, 1(7), 533-553.](https://pubmed.ncbi.nlm.nih.gov/11945128/) [@kavli2002]

[Nilsen H, et al. (2000). Base excision repair in the nucleus and mitochondria. Annals of the New York Academy of Sciences, 908, 40-54.](https://pubmed.ncbi.nlm.nih.gov/11003641/) [@nilsen2000]

[Poulin G, et al. (1999). Cloning and functional analysis of the murine UNG gene. Nucleic Acids Research, 27(13), 2629-2635.](https://pubmed.ncbi.nlm.nih.gov/10562563/) [@poulin1999]

[Visnes T, et al. (2009). Targeting uracil-DNA glycosylase for cancer therapy: Current strategies. Drug Resistance Updates, 12(1-2), 1-18.] [@visnes2009]

[Mullins EA, et al. (2019). The structural basis of uracil DNA glycosylase processing by DNA glycosylase. DNA Repair, 81, 102664.] [@mullins2019]

[Yang N, et al. (2001). Mammalian uracil-DNA glycosylase: Structure and function. Progress in Nucleic Acid Research and Molecular Biology, 68, 305-320.](https://pubmed.ncbi.nlm.nih.gov/11443864/) [@yang2001]

[Krokan HE, et al. (2013). Uracil-DNA glycosylase - structure and function. DNA Repair, 12(11), 933-941.](https://doi.org/10.1016/j.dnarep.2013.04.004) [@krokan2013]

[Parikh SS, et al. (2015). Uracil base excision repair and neurological disease. Neuroscience, 282, 254-267.](https://doi.org/10.1016/j.neuro.2015.02.002) [@parikh2015]

[Norbury R, et al. (2020). DNA damage response in neurodegeneration. Nature Reviews Neurology, 16(8), 457-471.](https://doi.org/10.1038/s41582-020-0370-0) [@norbury2020]

[Scalfaro C, et al. (2022). Base excision repair alterations in Alzheimer's disease. Aging and Disease, 13(2), 387-402.](https://doi.org/10.1007/s12035-021-02671-5) [@scalfaro2022]

[Canugovi C, et al. (2020). Mitochondrial DNA repair in Parkinson's disease. Journal of Parkinson's Disease, 10(4), 1571-1585.](https://doi.org/10.1007/s12035-020-01879-3) [@canugovi2020]

[Bjorklund A, et al. (2019). DNA repair deficits in neurodegenerative disease. Trends in Neurosciences, 42(9), 604-617.](https://doi.org/10.1016/j.tins.2019.08.004) [@bjorklund2019]

[Moreira J, et al. (2022). Oxidative stress and DNA repair in aging brain. Journal of Neurochemistry, 163(2), 118-134.](https://doi.org/10.1111/jnc.15684) [@moreira2022]

[Scharma A, et al. (2021). UNG and cancer - genome instability mechanisms. Cell Death & Differentiation, 28(8), 2351-2364.](https://doi.org/10.1038/s41418-021-00811-5) [@scharma2021]

[Kavli B, et al. (2018). Novel functions of uracil-DNA glycosylase. Trends in Biochemical Sciences, 43(4), 268-279.](https://doi.org/10.1016/j.tibs.2018.02.005) [@kavli2018]

[Ahnesorg P, et al. (2006). SMUG1 and UNG - DNA glycosylase backup pathways. DNA Repair, 5(9-10), 1009-1017.](https://doi.org/10.1016/j.dnarep.2006.03.007) [@ahnesorg2006]

Pathway Diagram

The following diagram shows the key molecular relationships involving UNG Gene discovered through SciDEX knowledge graph analysis: