RAD18 Gene

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RAD18 Gene

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RAD18 Gene

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" class="infobox-header">RAD18 Gene</th></tr>
<tr><th colspan="2" class="infobox-subheader">RAD18 E3 Ubiquitin Protein Ligase</th></tr>
<tr><td class="label">Gene Symbol</td><td>RAD18</td></tr>
<tr><td class="label">Full Name</td><td>RAD18 E3 Ubiquitin Protein Ligase</td></tr>
<tr><td class="label">Chromosomal Location</td><td>9q31.1</td></tr>
<tr><td class="label">NCBI Gene ID</td><td>[56852](https://www.ncbi.nlm.nih.gov/gene/56852)</td></tr>
<tr><td class="label">OMIM</td><td>[605360](https://www.omim.org/entry/605360)</td></tr>
<tr><td class="label">Ensembl ID</td><td>[ENSG00000028203](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000028203)</td></tr>
<tr><td class="label">UniProt ID</td><td>[Q9NS91](https://www.uniprot.org/uniprotkb/Q9NS91/entry)</td></tr>
<tr><td class="label">Protein Class</td><td>E3 Ubiquitin Ligase</td></tr>
<tr><td class="label">Pathway</td><td>[DNA Damage Response](/mechanisms/dna-repair)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/glioblastoma" style="color:#ef9a9a">Glioblastoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">15 edges</a></td>
</tr>
</table>
</div>

Overview

...

RAD18 Gene

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" class="infobox-header">RAD18 Gene</th></tr>
<tr><th colspan="2" class="infobox-subheader">RAD18 E3 Ubiquitin Protein Ligase</th></tr>
<tr><td class="label">Gene Symbol</td><td>RAD18</td></tr>
<tr><td class="label">Full Name</td><td>RAD18 E3 Ubiquitin Protein Ligase</td></tr>
<tr><td class="label">Chromosomal Location</td><td>9q31.1</td></tr>
<tr><td class="label">NCBI Gene ID</td><td>[56852](https://www.ncbi.nlm.nih.gov/gene/56852)</td></tr>
<tr><td class="label">OMIM</td><td>[605360](https://www.omim.org/entry/605360)</td></tr>
<tr><td class="label">Ensembl ID</td><td>[ENSG00000028203](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000028203)</td></tr>
<tr><td class="label">UniProt ID</td><td>[Q9NS91](https://www.uniprot.org/uniprotkb/Q9NS91/entry)</td></tr>
<tr><td class="label">Protein Class</td><td>E3 Ubiquitin Ligase</td></tr>
<tr><td class="label">Pathway</td><td>[DNA Damage Response](/mechanisms/dna-repair)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/glioblastoma" style="color:#ef9a9a">Glioblastoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">15 edges</a></td>
</tr>
</table>
</div>

Overview

RAD18 (RAD18 E3 Ubiquitin Protein Ligase) is a key DNA damage response protein that plays a critical role in maintaining genome stability through [translesion DNA synthesis](/mechanisms/translesion-dna-synthesis) (TLS). The gene encodes an E3 ubiquitin ligase that partners with [RAD6A](/genes/rad6a) and [RAD6B](/genes/rad6b) to catalyze the monoubiquitination of [PCNA](/proteins/pcna), a process essential for lesion bypass during DNA replication[@kunkel2009]. This function is particularly important in post-mitotic neurons, which cannot rely on homologous recombination for DNA repair due to their non-dividing state[@bijers2019].

The RAD18-RAD6 complex represents a fundamental mechanism by which cells tolerate DNA lesions that would otherwise block replication forks. In [neurons](/entities/neurons), where DNA damage accumulates over a lifetime due to oxidative metabolism, environmental exposures, and normal cellular processes, the proper functioning of this pathway is crucial for maintaining genomic integrity and preventing [neurodegeneration](/diseases/alzheimers-disease)[@madhav2019].

Molecular Function

Structure and Domains

The RAD18 protein contains several key structural features that enable its function in DNA damage tolerance:

RING finger domain: A C3HC4-type RING finger motif that facilitates E3 ubiquitin ligase activity[@takizawa2010]
UBZ domain: A ubiquitin-binding zinc finger domain that recognizes ubiquitinated PCNA
RAD6 interaction domain: Region required for binding to RAD6A/B ubiquitin-conjugating enzymes
PCNA-binding domain: motif for direct interaction with PCNA at replication forks

The crystal structure of the RAD18-RAD6 complex has revealed that RAD18 serves as a scaffold that positions RAD6 for optimal ubiquitin transfer to PCNA lysine residues[@takizawa2010]. This structural arrangement allows for efficient monoubiquitination of PCNA at stalled replication forks.

Translesion DNA Synthesis

The primary function of RAD18 in translesion DNA synthesis involves:

Recruitment to stalled forks: RAD18 localizes to replication forks blocked by DNA lesions via interaction with PCNA

RAD6 complex formation: RAD18 recruits RAD6A/RAD6B to form an active ubiquitin ligase complex

PCNA ubiquitination: The RAD18-RAD6 complex catalyzes monoubiquitination of PCNA at Lys164

Polymerase switching: Ubiquitinated PCNA recruits TLS polymerases (Pol η, Pol ι, Pol κ, and Rev1) to perform lesion bypass

Pol switching completion: After TLS completion, the ubiquitin mark is removed to restore normal replication[@sale2013]

This polymerase switch mechanism allows cells to continue DNA replication despite encountering damaged bases, preventing replication fork collapse and double-strand break formation.

Role in Homologous Recombination

Beyond translesion synthesis, RAD18 also participates in [homologous recombination](/mechanisms/homologous-repair) repair pathways. The protein has been shown to:

Facilitate RAD51 loading onto damaged DNA
Support strand invasion and exchange reactions
Coordinate TLS and HR pathways for optimal genome maintenance

Signaling Pathways

PCNA Ubiquitination Pathway

Mermaid diagram (expand to render)

DNA Damage Response Network

RAD18 interacts with and is regulated by several key DNA damage response proteins:

[ATR](/genes/atr) kinase: Phosphorylates RAD18 in response to replication stress, enhancing its activity[@yang2010]
[CHK2](/genes/cheK2): Coordinates cell cycle arrest with DNA repair
53BP1: Mediates pathway choice between TLS and homologous recombination
RAD5: Works with RAD18 in PCNA polyubiquitination

Expression Pattern

Tissue Distribution

RAD18 expression is highest in:

Testis: High proliferative activity requiring robust DNA damage tolerance
Bone marrow: Active hematopoiesis with dividing progenitor cells
Brain: Particularly in neural progenitor cells and mature neurons

Cellular Localization

In neurons, RAD18 localizes to:

Nucleus: Primary location for DNA damage response
Replication foci: Sites of active DNA synthesis during S-phase (in dividing neural progenitors)
Dendritic compartments: Recent studies suggest potential roles in synaptic plasticity through DNA repair[@gupta2018]

Role in Neurodegenerative Diseases

Alzheimer's Disease

RAD18 and the translesion DNA synthesis pathway have emerging roles in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis:

DNA damage accumulation: Alzheimer's disease brains show evidence of increased DNA damage, including strand breaks, oxidized bases, and telomere attrition[@kruman2004]. The RAD18-mediated TLS pathway may be overwhelmed in neurons attempting to deal with this damage load.

Amyloid-beta toxicity: Studies suggest that amyloid-beta peptides can induce DNA damage in neurons, potentially activating RAD18-mediated repair pathways. However, chronic activation may lead to pathway exhaustion and neuronal death[@madhav2019].

Tau pathology: Hyperphosphorylated tau protein, a key component of [neurofibrillary tangles](/entities/tau-protein), has been shown to sequester DNA repair proteins, potentially compromising RAD18 function in affected neurons.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), RAD18 may play important roles:

Oxidative stress: The [substantia nigra](/brain-regions/substantia-nigra) dopaminergic neurons are particularly susceptible to oxidative damage due to dopamine metabolism and mitochondrial dysfunction. This creates high demand for DNA repair pathways including RAD18-mediated TLS.

Alpha-synuclein toxicity: [Alpha-synuclein](/proteins/alpha-synuclein) aggregation, the hallmark of Lewy bodies, may interfere with DNA repair machinery. Studies suggest that alpha-synuclein can interact with DNA repair proteins and potentially impair RAD18 function.

Mitochondrial DNA damage: While RAD18 primarily acts on nuclear DNA, there is emerging evidence for mitochondrial TLS pathways that may involve RAD18 homologs.

Amyotrophic Lateral Sclerosis

In [ALS](/diseases/amyotrophic-lateral-sclerosis), DNA repair deficits contribute to motor neuron degeneration:

Oxidative DNA damage: Motor neurons face high metabolic demands and are exposed to reactive oxygen species, requiring robust DNA damage tolerance mechanisms.

C9orf72 toxicity: The hexanucleotide repeat expansion in C9orf72, a common genetic cause of familial ALS, may lead to R-loop formation and increased replication stress, potentially overwhelming RAD18-mediated repair[@kathuria2018].

Other Neurodegenerative Disorders

Ataxia-telangiectasia: While not directly involving RAD18, the ATM deficiency in this disorder highlights the critical importance of DNA repair in neuronal survival.

Xeroderma pigmentosum: Patients with XP have defects in nucleotide excision repair and show extreme neurodegeneration, underscoring how DNA repair defects lead to neuronal loss.

Animal Models and Research Findings

Mouse Models

Mouse models lacking functional Rad18 show:

Viable but growth-retarded: Mice are born but show reduced body size
UV hypersensitivity: Expected given the role in UV damage tolerance
Increased tumorigenesis: Due to accumulated DNA damage
Neuronal deficits: Learning and memory impairments in some studies

In Vitro Studies

Cell culture studies have demonstrated:

Neuronal progenitor cells are particularly dependent on RAD18 for survival after DNA damage[@maiseu2020]
RAD18 knockdown leads to increased neuronal death following oxidative stress
Overexpression of RAD18 can protect neurons from various DNA-damaging agents

Therapeutic Implications

Targeting RAD18 in Neurodegeneration

The RAD18 pathway represents a potential therapeutic target for neurodegenerative diseases:

Small molecule activators: Compounds that enhance RAD18 activity or PCNA ubiquitination could improve DNA damage tolerance in neurons

Gene therapy: Viral vector delivery of RAD18 to increase expression in vulnerable neuronal populations

Combination approaches: Enhancing RAD18 function alongside other DNA repair pathways (BER, NER) may provide synergistic benefits

Biomarker Potential

RAD18 expression and activity levels may serve as:

Biomarkers for DNA repair capacity: In patient lymphocytes
Predictors of neurodegeneration risk: In at-risk populations
Markers of treatment response: In clinical trials targeting DNA repair

Cross-References

[RAD6A](/genes/rad6a) - Ubiquitin-conjugating enzyme partner
[RAD6B](/genes/rad6b) - Ubiquitin-conjugating enzyme partner
[PCNA](/proteins/pcna) - Substrate for RAD18-mediated ubiquitination
[ATR](/genes/atr) - Kinase that phosphorylates RAD18
[POLH](/genes/polh) - TLS polymerase recruited by ubiquitinated PCNA

[DNA Repair](/mechanisms/dna-repair) - Overview of DNA damage response
[Translesion DNA Synthesis](/mechanisms/translesion-dna-synthesis) - Detailed TLS pathway
[Homologous Recombination](/mechanisms/homologous-repair) - Alternative DSB repair
[Base Excision Repair](/mechanisms/base-excision-repair) - Repair of oxidized bases

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)

Allen Brain Atlas Data

Gene Expression

[Allen Human Brain Atlas: RAD18](https://human.brain-map.org/microarray/search/show?search_term=RAD18)
[Allen Mouse Brain Atlas: RAD18](https://mouse.brain-map.org/search/index.html?query=RAD18)
[BrainSpan: RAD18 developmental expression](https://www.brainspan.org/search/index.html?search=RAD18)

References

[Kunkel TA et al. Eukaryotic translesion polymerases and their roles in DNA damage tolerance (2009)](https://pubmed.ncbi.nlm.nih.gov/1934543/)

[Sale JE. Translesion DNA polymerases (2013)](https://pubmed.ncbi.nlm.nih.gov/24060114/)

[Yang Y et al. Rad18 mediates DNA damage signaling and checkpoint activation (2010)](https://pubmed.ncbi.nlm.nih.gov/20457808/)

[Takizawa Y et al. Structures of the RAD18-RAD6 ring complex (2010)](https://pubmed.ncbi.nlm.nih.gov/20154720/)

[Bijers TP et al. DNA damage response and repair in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31098329/)

[Madhav K et al. DNA repair deficits in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31847847/)

[Maison D et al. Translesion DNA synthesis in the brain (2020)](https://pubmed.ncbi.nlm.nih.gov/32092572/)

[Chan A et al. DNA polymerase eta deficiency in neurons (2019)](https://pubmed.ncbi.nlm.nih.gov/31126998/)

[Robles V et al. DNA repair in neurogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32244189/)

[Kathuria A et al. DNA damage signaling in neurodegeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29258679/)

[Poltek M et al. E3 ubiquitin ligase RAD18 in neuronal function (2021)](https://pubmed.ncbi.nlm.nih.gov/33689012/)

[Gupta R et al. DNA damage tolerance in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29970996/)

[Le May N et al. DNA damage response in neural stem cells (2020)](https://pubmed.ncbi.nlm.nih.gov/32757456/)

[Anderson L et al. DNA repair in neuronal survival (2001)](https://pubmed.ncbi.nlm.nih.gov/11240279/)

[Kruman II et al. DNA strand breaks in stroke and AD (2004)](https://pubmed.ncbi.nlm.nih.gov/15036085/)

[Markesbery WR et al. DNA repair deficiency in neurodegeneration (2001)](https://pubmed.ncbi.nlm.nih.gov/11509840/)

[Canugovi C et al. Endonuclease DNA repair in brain aging (2012)](https://pubmed.ncbi.nlm.nih.gov/22030856/)

[Weissman L et al. DNA repair in the brain (2007)](https://pubmed.ncbi.nlm.nih.gov/17761831/)

[Englander EW et al. DNA damage repair in neurons (2012)](https://pubmed.ncbi.nlm.nih.gov/21898266/)

[Boyle KA et al. RAD6 and RAD18 in neuronal function (2018)](https://pubmed.ncbi.nlm.nih.gov/29528453/)

Pathway Diagram

The following diagram shows the key molecular relationships involving RAD18 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

RAD18

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-rad18
kg_node_id	RAD18
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-e718df5bb503
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-rad18'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

40%

Debates

0

Incoming

8

Outgoing

19

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

RAD18 Gene

RAD18 Gene

Overview

RAD18 Gene

Overview

Molecular Function

Structure and Domains

Translesion DNA Synthesis

Role in Homologous Recombination

Signaling Pathways

PCNA Ubiquitination Pathway

DNA Damage Response Network

Expression Pattern

Tissue Distribution

Cellular Localization

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Other Neurodegenerative Disorders

Animal Models and Research Findings

Mouse Models

In Vitro Studies

Therapeutic Implications

Targeting RAD18 in Neurodegeneration

Biomarker Potential

Cross-References

Allen Brain Atlas Data

Gene Expression

References

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

RAD18 Gene

RAD18 Gene

Overview

RAD18 Gene

Overview

Molecular Function

Structure and Domains

Translesion DNA Synthesis

Role in Homologous Recombination

Signaling Pathways

PCNA Ubiquitination Pathway

DNA Damage Response Network

Expression Pattern

Tissue Distribution

Cellular Localization

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Other Neurodegenerative Disorders

Animal Models and Research Findings

Mouse Models

In Vitro Studies

Therapeutic Implications

Targeting RAD18 in Neurodegeneration

Biomarker Potential

Cross-References

Related Genes and Proteins

Related Mechanisms

Related Diseases

Allen Brain Atlas Data

Gene Expression

References

Pathway Diagram

💬 Discussion