RAD18 Protein — DNA Damage Repair and Translesion Synthesis

RAD18 Protein — DNA Damage Repair and Translesion Synthesis

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">RAD18 Protein — DNA Damage Repair and Translesion Synthesis</th>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">[PCNA](/proteins/pcna-protein)</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">[RAD6A/RAD6B](/proteins/rad6a-protein)</td>
<td>Complex formation</td>
</tr>
<tr>
<td class="label">[Pol η](/proteins/polh-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Pol ι](/proteins/poli-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Pol κ](/proteins/polk-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Rev1](/proteins/rev1-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[RAD51](/proteins/rad51-protein)</td>
<td>HR coordination</td>
</tr>
<tr>
<td class="label">[ATR](/proteins/atr-protein)</td>
<td>Damage signaling</td>
</tr>
<tr>
<td class="label">[ATM](/proteins/atm-protein)</td>
<td>Damage signaling</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

RAD18 Protein — DNA Damage Repair and Translesion Synthesis

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">RAD18 Protein — DNA Damage Repair and Translesion Synthesis</th>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">[PCNA](/proteins/pcna-protein)</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">[RAD6A/RAD6B](/proteins/rad6a-protein)</td>
<td>Complex formation</td>
</tr>
<tr>
<td class="label">[Pol η](/proteins/polh-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Pol ι](/proteins/poli-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Pol κ](/proteins/polk-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[Rev1](/proteins/rev1-protein)</td>
<td>Polymerase recruitment</td>
</tr>
<tr>
<td class="label">[RAD51](/proteins/rad51-protein)</td>
<td>HR coordination</td>
</tr>
<tr>
<td class="label">[ATR](/proteins/atr-protein)</td>
<td>Damage signaling</td>
</tr>
<tr>
<td class="label">[ATM](/proteins/atm-protein)</td>
<td>Damage signaling</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>

RAD18 is a DNA-dependent ATPase and E3 ubiquitin ligase that plays a critical role in maintaining genomic integrity. It is a key regulator of the DNA damage response (DDR), particularly in translesion synthesis (TLS) and the repair of DNA double-strand breaks. RAD18 is essential for bypassing DNA lesions that would otherwise block replication, preventing replication fork collapse and cell death. In [neurons](/entities/neurons), which are post-mitotic and particularly vulnerable to DNA damage accumulation, RAD18-mediated DNA repair is crucial for neuronal survival and function.

Structure

RAD18 is a 495-amino acid protein with multiple functional domains:

The human RAD18 protein is encoded by the RAD18 gene located on chromosome 3p24-25.

Function in DNA Damage Repair

Translesion Synthesis (TLS)

RAD18's primary function is to orchestrate translesion synthesis, a DNA damage tolerance mechanism that allows replication past DNA lesions:

• PCNA (monoubiquitinated) → PCNA-Ub
• This modification switches DNA polymerase usage from high-fidelity replicative polymerases to error-prone TLS polymerases

• [Pol η](/proteins/polh-protein) (eta) — inserts nucleotides opposite UV-induced lesions
• [Pol ι](/proteins/poli-protein) (iota) — extends mispaired primers
• [Pol κ](/proteins/polk-protein) (kappa) — bypasses bulky adducts
• [Rev1](/proteins/rev1-protein) — inserts cytosine opposite damaged bases

PCNA Polyubiquitination

Beyond monoubiquitination, RAD18 also catalyzes K63-linked polyubiquitination of [PCNA](/proteins/pcna-protein):

• This leads to an alternative damage tolerance pathway called template switching
• Involves the [RAD5](/proteins/rad5-protein) protein and other TLS factors
• Uses the sister's chromatid as a template for error-free repair

Role in Homologous Recombination

RAD18 also participates in homologous recombination (HR) repair:

• Facilitates [RAD51](/proteins/rad51-protein) filament formation
• Promotes strand invasion during HR
• Helps coordinate TLS and HR pathways

Role in Neurodegenerative Diseases

DNA Damage in Neurodegeneration

Neurons accumulate DNA damage over time due to:

• [Reactive oxygen species](/entities/reactive-oxygen-species) (ROS) from mitochondrial metabolism
• Exogenous genotoxic insults
• Impaired DNA repair mechanisms
• Aging-related decline in repair capacity

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease):

• DNA damage accumulation: Elevated levels of DNA strand breaks, oxidized bases, and DNA adducts are observed in AD brain
• Impaired repair: RAD18 expression and activity may be reduced in AD neurons
• Aβ toxicity: [Amyloid-beta](/proteins/amyloid-beta) peptides can induce DNA damage and impair DNA repair
• Therapeutic potential: Enhancing RAD18-mediated repair could protect neurons from DNA damage-induced death

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease):

• Oxidative stress: Dopaminergic neurons face high oxidative stress; ROS cause DNA damage
• Mitochondrial DNA: [Alpha-synuclein](/proteins/alpha-synuclein) aggregation may affect nuclear DNA repair
• DNA repair deficits: RAD18 dysfunction may contribute to dopaminergic neuron loss
• Neuroprotection: Enhancing RAD18 could protect [dopaminergic neurons](/cell-types/dopaminergic-neurons)

Huntington's Disease

In [Huntington's disease](/diseases/huntingtons):

• Mutant [huntingtin](/proteins/huntingtin) toxicity: The polyglutamine-expanded [huntingtin](/proteins/huntingtin) protein causes transcriptional dysregulation and DNA damage
• Repair impairment: RAD18 and other DNA repair proteins may be sequestered or dysfunctional
• Therapeutic targeting: Restoring DNA repair capacity through RAD18 modulation is being explored

Aging and Neuronal Decline

• Age-related decline: RAD18 activity declines with age, compromising DNA repair
• Accumulated damage: Neuronal DNA damage accumulates over lifespan
• Cognitive decline: DNA damage in neurons correlates with age-related cognitive decline
• Interventions: Enhancing RAD18 function may slow age-related neurodegeneration

Signaling Pathways

ATR-Chk1 Pathway

• [ATR](/proteins/atr-protein) (Ataxia Telangiectasia and Rad3-related) phosphorylates [Chk1](/proteins/chk1-protein)
• This coordinates cell cycle arrest with DNA repair
• RAD18 activation is part of this checkpoint response

ATM-Chk2 Pathway

• [ATM](/proteins/atm-protein) (Ataxia Telangiectasia Mutated) responds to double-strand breaks
• Activates [Chk2](/proteins/chk2-protein) and p53
• Cross-talk between ATM and RAD18 in DSB repair

p53-Dependent Response

• [p53](/proteins/p53-protein) regulates DNA damage responses
• p53 can influence RAD18 expression
• Coordinates DNA repair with [apoptosis](/entities/apoptosis)

Interaction Network

Therapeutic Implications

Neuroprotective Strategies

• Small molecule activators: Compounds that enhance RAD18 activity or expression
• Gene therapy: Viral vector-mediated RAD18 delivery to neurons
• Combination approaches: RAD18 enhancement with other DNA repair proteins

DNA Repair Enhancement

• Poly(ADP-ribose) polymerase (PARP) inhibitors: May complement RAD18 function
• Antioxidants: Reduce DNA damage burden, easing repair demands
• Telomere maintenance: Related DNA repair pathways

Aging and Longevity

• DNA repair decline: Aging is associated with impaired DNA repair
• Interventions: Enhancing RAD18 could slow age-related cognitive decline
• Preventive therapy: Early-life DNA repair enhancement may prevent neurodegeneration

See Also

• [Alzheimer's disease](/diseases/alzheimers-disease)
• [Parkinson's disease](/diseases/parkinsons-disease)
• [Huntington's disease](/diseases/huntingtons)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References