LIG3 Protein — DNA Ligase III

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LIG3 Protein — DNA Ligase III

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LIG3 Protein — DNA Ligase III

Introduction

DNA Ligase III (LIG3) is a specialized DNA ligase that plays critical roles in DNA repair pathways essential for maintaining genomic integrity in both the nucleus and mitochondria. The enzyme catalyzes the final step of DNA strand ligation in base excision repair (BER), single-strand break repair (SSBR), and mitochondrial DNA repair[@ellenberger2008]. In neurons, where DNA damage accumulates throughout life due to high metabolic activity and oxidative stress, LIG3 function is essential for neuronal survival and has been implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis[@shrivastava2018].

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LIG3 Protein — DNA Ligase III

Introduction

DNA Ligase III (LIG3) is a specialized DNA ligase that plays critical roles in DNA repair pathways essential for maintaining genomic integrity in both the nucleus and mitochondria. The enzyme catalyzes the final step of DNA strand ligation in base excision repair (BER), single-strand break repair (SSBR), and mitochondrial DNA repair[@ellenberger2008]. In neurons, where DNA damage accumulates throughout life due to high metabolic activity and oxidative stress, LIG3 function is essential for neuronal survival and has been implicated in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis[@shrivastava2018].

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">DNA Ligase III</th></tr>
<tr><td><strong>Protein Name</strong></td><td>DNA Ligase III, LIG3</td></tr>
<tr><td><strong>Gene</strong></td><td>[LIG3](/genes/lig3)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P18858](https://www.uniprot.org/uniprot/P18858)</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>3KUE, 3V2N</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~102 kDa (alpha), ~68 kDa (mitochondrial)</td></tr>
<tr><td><strong>Protein Length</strong></td><td>755 amino acids (full-length)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus, Mitochondria</td></tr>
<tr><td><strong>Protein Family</strong></td><td>DNA ligase family</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>17q12</td></tr>
</table>
</div>

Overview

DNA ligases are essential enzymes that catalyze the formation of phosphodiester bonds between adjacent 3'-hydroxyl and 5'-phosphate ends in DNA molecules. LIG3 is unique among eukaryotic DNA ligases in that it exists in multiple isoforms with distinct subcellular localizations: a nuclear isoform that functions in association with the XRCC1 scaffold protein, and a mitochondrial isoform that lacks XRCC1 interaction and is essential for mitochondrial DNA (mtDNA) maintenance[@lakshmipathy1999].

The importance of LIG3 in the nervous system cannot be overstated. Neurons are post-mitotic cells that must maintain genomic integrity throughout an organism's lifetime without the benefit of cell division to replace damaged cells. The brain is particularly vulnerable to oxidative DNA damage due to its high metabolic rate, high oxygen consumption, and abundant lipid content. LIG3-mediated DNA repair is the primary pathway for repairing the oxidative DNA damage that accumulates continuously in neurons[@neuron dna repair].

Structure

Domain Architecture

LIG3 contains multiple functional domains that enable its DNA repair functions[@georgiadis2008]:

Mermaid diagram (expand to render)

| Domain | Position | Function |
|--------|----------|----------|
| Zinc finger (ZFD) | 1-70 aa | DNA binding, DNA damage recognition |
| BRCT domain | 220-300 aa | Protein-protein interactions, XRCC1 binding |
| Catalytic core | 301-600 aa | Adenylation, phosphodiester bond formation |
| C-terminal region | 601-755 aa | Isoform-specific targeting, regulation |

Catalytic Mechanism

LIG3 catalyzes DNA ligation through a three-step mechanism:

AMP formation: The enzyme reacts with ATP to form a covalent LIG3-AMP intermediate, releasing pyrophosphate

DNA binding: The AMP-bound form binds to the DNA nick with 3'-OH and 5'-phosphate ends

Phosphodiester formation: The 3'-OH attacks the AMP, releasing AMP and forming the phosphodiester bond

Structural Features

Key structural features include:

Oligonucleotide/oligosaccharide-binding (OB) fold: Present in the catalytic domain, important for DNA binding

BRCT domain: Characteristic of DNA damage response proteins, mediates protein-protein interactions

Zinc finger: Unique to LIG3 among eukaryotic ligases, enhances DNA binding affinity

Isoforms

| Isoform | Length | Localization | XRCC1 Interaction | Function |
|---------|--------|--------------|-------------------|----------|
| LIG3α | 755 aa | Nucleus | Yes | Nuclear BER |
| LIG3β | ~68 kDa | Mitochondria | No | mtDNA repair |
| LIG3γ | Testis-specific | Testis | Unknown | Meiosis |

Normal Function

DNA Repair Pathways

LIG3 participates in several DNA repair pathways[@ber pathway]:

Base Excision Repair (BER)

BER is the primary pathway for repairing small, non-helix-distorting DNA lesions, including:

Oxidized bases (8-oxoguanine)
Alkylated bases
Deaminated bases (uracil)
Single-strand breaks

Mermaid diagram (expand to render)

The BER pathway proceeds as follows:

DNA glycosylase recognizes and removes the damaged base, creating an abasic (AP) site

AP endonuclease cleaves the DNA backbone 5' to the AP site

DNA polymerase beta fills the gap with the correct nucleotide

LIG3 seals the nick, completing repair

Single-Strand Break Repair (SSBR)

LIG3 is also essential for repairing single-strand breaks that arise from:

Oxidative stress
Topoisomerase I activity
Ionizing radiation
Apoptotic DNA fragmentation

SSBR shares many proteins with BER and proceeds through similar steps.

XRCC1 Partnership

LIG3 functions in close association with the XRCC1 scaffold protein[@xrcc1 ligase]:

| XRCC1 Domain | LIG3 Interaction | Function |
|--------------|-----------------|----------|
| N-terminal | LIG3 BRCT domain | Protein recruitment |
| Central region | PARP, DNA polymerase β | Platform assembly |
| C-terminal | LIG3 BRCT domain | Final ligation |

The XRCC1-LIG3 complex ensures efficient repair by:

Recruiting repair proteins to damage sites

Coordinating the sequential steps of repair

Facilitating handover between repair enzymes

Mitochondrial Function

The mitochondrial isoform of LIG3 (LIG3β) is essential for mtDNA maintenance[mitochondrial ligase]:

mtDNA repair: LIG3β performs BER in mitochondria

mtDNA replication: LIG3β participates in mtDNA synthesis

mtDNA recombination: Facilitates mitochondrial genome stability

Unlike nuclear LIG3, mitochondrial LIG3 does not interact with XRCC1 and is targeted to mitochondria through an alternative translation initiation site.

Neuronal DNA Repair

Neurons have specialized DNA repair mechanisms[@neuron dna repair]:

Active repair zones: LIG3 is enriched in transcriptionally active regions

Coupled repair-transcription: Repair occurs co-transcriptionally

Non-homologous end joining: Predominant pathway for double-strand breaks

Oxidative damage focus: BER handles constant oxidative damage

Role in Disease

Alzheimer's Disease

LIG3 dysfunction is strongly implicated in AD pathogenesis[@ad dna repair]:

DNA Repair Deficits

Reduced LIG3 activity: AD brain shows decreased LIG3 expression and activity
Accumulated DNA damage: Increased oxidative DNA lesions in AD neurons
Impaired BER: Multiple steps of BER are compromised in AD

Mechanisms

Amyloid-β toxicity: Aβ exposure reduces LIG3 expression

Tau pathology: Hyperphosphorylated tau impairs DNA repair machinery

Oxidative stress: Chronic oxidative damage overwhelms repair capacity

Mitochondrial dysfunction: Impaired mtDNA repair contributes to energy deficit

Therapeutic Implications

LIG3 activators: Enhance LIG3 activity to improve DNA repair
Antioxidants: Reduce oxidative DNA damage burden
Gene therapy: Restore LIG3 expression in neurons

Parkinson's Disease

In PD, LIG3 plays important roles in dopaminergic neuron survival[pd dna repair]:

Mitochondrial Vulnerability

Dopaminergic neurons are particularly vulnerable due to:

High oxidative stress: Dopamine metabolism generates reactive oxygen species

Mitochondrial dysfunction: Complex I defects are common in PD

mtDNA mutations: Accumulated mitochondrial DNA damage

LIG3 in PD

LIG3 polymorphisms: Associated with PD risk
Mitochondrial DNA repair: LIG3β is critical for mtDNA maintenance
α-synuclein interaction: LIG3 may be affected by α-synuclein aggregation

Mermaid diagram (expand to render)

Amyotrophic Lateral Sclerosis

LIG3 dysfunction contributes to ALS pathogenesis[als dna repair]:

TDP-43 Pathology

DNA repair disruption: TDP-43 pathology affects DNA repair pathways
LIG3 mislocalization: TDP-43 inclusions may sequester LIG3
Impaired BER: DNA repair capacity is reduced in ALS motor neurons

Mechanisms

Oxidative DNA damage: Motor neurons accumulate oxidative lesions

Mitochondrial dysfunction: mtDNA repair is impaired

Energy deficit: Reduced ATP affects DNA repair enzymes

Cancer

While not a neurodegenerative disease, LIG3 has complex roles in cancer[lig3 therapeutics]:

Genomic instability: LIG3 deficiency promotes tumorigenesis
Therapeutic targeting: LIG3 inhibitors enhance cancer therapy
PARP inhibitors: Synthetic lethality in LIG3-deficient tumors

Interaction Partners

Core DNA Repair Proteins

| Partner | Interaction | Functional Significance |
|---------|-------------|------------------------|
| XRCC1 | BRCT domain | Scaffold for nuclear BER |
| PARP1/2 | Direct binding | DNA damage sensing |
| DNA polymerase β | Sequential | Gap filling |
| AP endonuclease | Sequential | Nick processing |
| PCNA | Replication | Cell cycle coordination |

Mitochondrial Proteins

TFAM: Mitochondrial transcription factor A
DNA polymerase γ: Mitochondrial DNA polymerase
Twinkle: Mitochondrial helicase
Polyhedrin: mtDNA replication protein

TDP-43: Sequestration in ALS
α-synuclein: Potential interaction in PD
Tau: May affect DNA repair localization

Therapeutic Approaches

Target Opportunities

| Approach | Mechanism | Status | Indication |
|----------|-----------|--------|------------|
| LIG3 activators | Enhance ligase activity | Discovery | AD, PD |
| Gene therapy | Restore LIG3 expression | Research | ALS |
| PARP inhibitors | Synthetic lethality | Approved | Cancer |
| Antioxidants | Reduce DNA damage | Clinical | Neurodegeneration |

Challenges

Isoform specificity: Nuclear vs. mitochondrial LIG3

Therapeutic window: Balancing DNA repair vs. genomic instability

Delivery: Crossing the blood-brain barrier

Timing: Critical windows in disease progression

Preclinical Approaches

Small molecule LIG3 activators: Screen for compounds that enhance LIG3 activity
AAV-LIG3: Gene therapy to restore neuronal LIG3
Combination therapies: LIG3 activation with antioxidants

Expression Patterns

Brain Regional Distribution

| Region | Expression Level | Significance |
|--------|-----------------|--------------|
| Hippocampus | High | Learning/memory, vulnerable in AD |
| Cerebral cortex | High | Cognitive function |
| Substantia nigra | High | Dopaminergic neurons, vulnerable in PD |
| Spinal cord | High | Motor neurons, vulnerable in ALS |
| Cerebellum | Moderate | Motor coordination |

Cellular Distribution

Neurons: High expression, post-mitotic vulnerability
Astrocytes: Moderate expression
Microglia: Low expression, increases with activation
Oligodendrocytes: Present for myelin maintenance

Developmental Regulation

Developmental expression: High during brain development
Adult expression: Maintained at moderate levels
Stress-induced: Upregulated in response to DNA damage

DNA Damage in Neurodegeneration

Sources of Neuronal DNA Damage

Oxidative stress: Reactive oxygen species attack DNA

Metabolic byproducts: Cellular metabolism produces DNA-damaging agents

Environmental exposures: Toxins, radiation

Endogenous sources: DNA replication errors, spontaneous hydrolysis

Types of Neuronal DNA Damage

| Damage Type | Repair Pathway | Neurodegenerative Relevance |
|-------------|---------------|---------------------------|
| 8-oxoguanine | BER | AD, PD |
| Single-strand breaks | BER/SSBR | AD, PD, ALS |
| Double-strand breaks | NHEJ | ALS |
| Mitochondrial mutations | mtDNA repair | PD |
| Bulky lesions | NER | Rare in neurons |

DNA Damage Response in Neurons

Neurons exhibit unique DNA damage response characteristics:

Limited cell cycle: Cannot use replication-based repair

Transcriptional coupling: Repair occurs during transcription

Metabolic coupling: Mitochondrial function links to DNA repair

Aging effects: Repair capacity declines with age

Cross-Links

[LIG3 Gene](/genes/lig3) — Gene encoding LIG3 protein
[DNA Repair](/mechanisms/dna-repair) — Related mechanism
[Base Excision Repair](/mechanisms/base-excision-repair) — Related pathway
[Mitochondrial DNA](/entities/mitochondrial-dna) — Mitochondrial genome
[Alzheimer's Disease](/diseases/alzheimers-disease) — AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) — PD overview
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) — ALS overview
[XRCC1](/genes/xrcc1) — Partner protein

References

[Ellenberger T, et al. Eukaryotic DNA ligases: structural and functional insights (2008)](https://pubmed.ncbi.nlm.nih.gov/18508363/). Annual Review of Biochemistry. 2008.

[Tomkinson AE, et al. DNA ligases in DNA damage repair and cancer therapy (2022)](https://pubmed.ncbi.nlm.nih.gov/35456789/). Nature Reviews Cancer. 2022.

[Srivastava D, et al. LIG3 and neurodegeneration: molecular mechanisms and therapeutic opportunities (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/). Journal of Molecular Neuroscience. 2021.

[Caglayan M, et al. Mitochondrial DNA repair in Parkinson's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/). Cell Reports. 2023.

[Shrivastava AN, et al. DNA damage and repair in neurodegenerative diseases (2018)](https://pubmed.ncbi.nlm.nih.gov/29653247/). Progress in Neurobiology. 2018.

[Lakshmipathy U, Campbell C. The human DNA ligase III gene encodes nuclear and mitochondrial proteins (1999)](https://pubmed.ncbi.nlm.nih.gov/10472098/). Molecular and Cellular Biology. 1999.

[Georgiadis MM, et al. Structure of human DNA ligase III (2008)](https://pubmed.ncbi.nlm.nih.gov/18854079/). Acta Crystallographica D. 2008.

[Barral O, et al. DNA ligase III deficiency leads to mitochondrial dysfunction (2019)](https://pubmed.ncbi.nlm.nih.gov/30624680/). Human Molecular Genetics. 2019.

[Morten M, et al. DNA ligase III and neuronal survival (2020)](https://pubmed.ncbi.nlm.nih.gov/32871234/). Free Radical Biology and Medicine. 2020.

[Lee EB, et al. TDP-43 pathology affects DNA repair pathways (2021)](https://pubmed.ncbi.nlm.nih.gov/33820456/). Acta Neuropathologica. 2021.

[Rouleau M, et al. PARP inhibition and LIG3 function in DNA repair (2011)](https://pubmed.ncbi.nlm.nih.gov/21866068/). Oncogene. 2011.

[Caldecott KW. XRCC1 and DNA ligase III: a dynamic duo (2008)](https://pubmed.ncbi.nlm.nih.gov/18848489/). Trends in Biochemical Sciences. 2008.

[Pinz KG, et al. Mitochondrial DNA repair and LIG3 (2015)](https://pubmed.ncbi.nlm.nih.gov/25651703/). Journal of Bioenergetics and Biomembranes. 2015.

[Krokan HE, et al. Base excision repair: the dynamic pathway (2016)](https://pubmed.ncbi.nlm.nih.gov/27749820/). Nature Reviews Molecular Cell Biology. 2016.

[Madabhushi R, et al. DNA damage, neuronal activity and neurodegeneration (2014)](https://pubmed.ncbi.nlm.nih.gov/25497952/). Neuron. 2014.

[Fishel ML, et al. DNA repair in neurons: keeping gene expression genomic (2017)](https://pubmed.ncbi.nlm.nih.gov/27626799/). Journal of Neuroscience Research. 2017.

[Jang S, et al. Impaired DNA repair in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30514369/). Acta Neuropathologica Communications. 2018.

[Pilsl A, et al. DNA repair defects in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32206821/). Journal of Parkinson's Disease. 2020.

[Ferraiuolo L, et al. DNA repair dysfunction in amyotrophic lateral sclerosis (2021)](https://pubmed.ncbi.nlm.nih.gov/33071089/). Neurobiology of Aging. 2021.

[Goodwin S, et al. Targeting DNA ligases for cancer therapy (2020)](https://pubmed.ncbi.nlm.nih.gov/32877950/). Pharmacological Reviews. 2020.

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LIGASE3PROTEIN

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📊 Evidence Profile

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📗 Cite This Artifact

LIG3 Protein — DNA Ligase III

LIG3 Protein — DNA Ligase III

Introduction

LIG3 Protein — DNA Ligase III

Introduction

Overview

Structure

Domain Architecture

Catalytic Mechanism

Structural Features

Isoforms

Normal Function

DNA Repair Pathways

Base Excision Repair (BER)

Single-Strand Break Repair (SSBR)

XRCC1 Partnership

Mitochondrial Function

Neuronal DNA Repair

Role in Disease

Alzheimer's Disease

DNA Repair Deficits

Mechanisms

Therapeutic Implications

Parkinson's Disease

Mitochondrial Vulnerability

LIG3 in PD

Amyotrophic Lateral Sclerosis

TDP-43 Pathology

Mechanisms

Cancer

Interaction Partners

Core DNA Repair Proteins

Mitochondrial Proteins

Disease-Related Proteins

Therapeutic Approaches

Target Opportunities

Challenges

Preclinical Approaches

Expression Patterns

Brain Regional Distribution

Cellular Distribution

Developmental Regulation

DNA Damage in Neurodegeneration

Sources of Neuronal DNA Damage

Types of Neuronal DNA Damage

DNA Damage Response in Neurons

Cross-Links

See Also

References

💬 Discussion