RPA3

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RPA3

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RPA3

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">RPA3</th></tr>
<tr><td><b>Full Name</b></td><td>Replication Protein A3</td></tr>
<tr><td><b>Symbol</b></td><td>RPA3</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>7q32.3</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[6731](https://www.ncbi.nlm.nih.gov/gene/6731)</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000186871</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P35274](https://www.uniprot.org/uniprot/P35274)</td></tr>
<tr><td><b>Associated Diseases</b></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td></tr>
</table>
</div>

Introduction

...

RPA3

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">RPA3</th></tr>
<tr><td><b>Full Name</b></td><td>Replication Protein A3</td></tr>
<tr><td><b>Symbol</b></td><td>RPA3</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>7q32.3</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>[6731](https://www.ncbi.nlm.nih.gov/gene/6731)</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000186871</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P35274](https://www.uniprot.org/uniprot/P35274)</td></tr>
<tr><td><b>Associated Diseases</b></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td></tr>
</table>
</div>

Introduction

Mermaid diagram (expand to render)

RPA3 (Replication Protein A3) is a subunit of the heterotrimeric Replication Protein A complex (RPA), the major single-stranded DNA (ssDNA)-binding protein in eukaryotic cells. RPA plays essential roles in DNA replication, repair, recombination, and the DNA damage response. While RPA3 is the smallest subunit, it is essential for complex stability and function. Recent research has revealed important connections between RPA dysfunction and neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), where DNA damage accumulation and impaired DNA repair are key pathological features [1][2].

This page covers the gene's normal molecular function, structure, disease associations, expression patterns, and implications for neurodegeneration research.

Normal Function

The RPA Complex

RPA is a heterotrimeric complex composed of:

RPA1 (RPA70): 70 kDa subunit - contains multiple DNA-binding domains (DBDs) and protein interaction domains
RPA2 (RPA32): 32 kDa subunit - phosphorylated in response to DNA damage, regulates protein interactions
RPA3 (RPA14): 14 kDa subunit - smallest subunit, essential for complex assembly and stability

The RPA complex binds with high affinity to ssDNA, forming a protective shield that prevents:

Secondary structure formation
Nucleolytic degradation
Unwanted recombination

DNA Replication Functions

RPA is essential for DNA replication:

Origin Recognition and Activation

RPA helps unwind DNA at replication origins
Interacts with origin recognition complex (ORC)
Loads replication factors onto single-stranded DNA
Facilitates minichromosome maintenance (MCM) complex loading

Leading and Lagging Strand Synthesis

Provides ssDNA template protection
Interacts with DNA polymerases (Pol α, δ, ε)
Coordinates primer synthesis and extension
Regulates replication fork progression

Replication Stress Response

Stalls forks at DNA damage sites
Activates checkpoint signaling
Prevents fork collapse
Facilitates fork restart

DNA Repair Functions

RPA participates in multiple DNA repair pathways:

Nucleotide Excision Repair (NER)

Initial damage recognition
Helicase loading (XPA, XPF)
Gap filling coordination

Base Excision Repair (BER)

Single-strand break recognition
Gap filling coordination
DNA ligase recruitment

Homologous Recombination (HR)

Resection monitoring
RAD51 filament formation regulation
Strand invasion assistance

Mismatch Repair (MMR)

Mismatch detection coordination
Strand discrimination
Excision and resynthesis

DNA Damage Response

RPA is a central sensor of DNA damage:

Damage Recognition

Binds directly to ssDNA generated by damage
Recognizes stalled replication forks
Detects gaps and breaks

Checkpoint Activation

Activates ATR/ATRIP kinase pathway
Phosphorylates CHK1 and CHK2
Coordinates cell cycle arrest

Signaling Scaffold

Recruits repair proteins to damage sites
Modulates chromatin accessibility
Coordinates repair pathway choice

Telomere Maintenance

RPA functions at telomeres:

Protects telomeric ssDNA
Facilitates telomere replication
Prevents telomere dysfunction
Works with shelterin complex

Molecular Structure

RPA3 Protein Structure

RPA3 (14 kDa) contains:

N-terminal domain: Essential for complex formation
Central region: Interacts with RPA1 and RPA2
C-terminal region: Dimerization interface

The protein forms a tight heterotrimer with RPA1 and RPA2, requiring all three subunits for stable complex formation.

Post-Translational Modifications

RPA3 is subject to:

Phosphorylation: By ATM/ATR/DNA-PK in response to damage
Acetylation: Regulates protein-protein interactions
SUMOylation: Affects subcellular localization
Ubiquitination: Targets for degradation

Disease Associations

Alzheimer's Disease

RPA3 connects to AD through multiple mechanisms:

DNA Damage Accumulation

AD neurons show:

Elevated levels of oxidative DNA damage
Accumulation of DNA double-strand breaks
Impaired repair of neuronal DNA damage
Telomere shortening

DNA Repair Deficits

Decreased RPA focus formation in AD brains
Impaired ATR signaling
Reduced CHK1 activation
Compromised checkpoint function

Connection to Amyloid Pathology

Aβ peptides can cause DNA damage directly
RPA recruitment is impaired in Aβ-treated cells
Amyloid plaques are surrounded by DNA damage

Tau Pathology Interaction

Phosphorylated tau affects DNA repair proteins
RPA mislocalization in tauopathy neurons
Synaptic DNA damage accumulation

Parkinson's Disease

RPA3 involvement in PD:

Dopaminergic Neuron Vulnerability

High metabolic demands = high DNA damage
Limited DNA repair capacity
Mitochondrial dysfunction increases damage
Alpha-synuclein affects DNA repair

Mitochondrial DNA

mtDNA damage accumulates in PD
RPA may be involved in mtDNA repair
PINK1/Parkin pathway intersects with DNA damage response

LRRK2 Connection

LRRK2 mutations increase DNA damage sensitivity
RPA phosphorylation affected by LRRK2
G2019S mutation impairs checkpoint recovery

Other Neurodegenerative Diseases

ALS

DNA damage is a consistent finding
RPA foci form in motor neurons
TDP-43 pathology affects DNA repair

Huntington's Disease

CAG repeat expansions cause DNA damage
RPA recruitment is impaired
DNA repair is a therapeutic target

Ataxia Telangiectasia

ATM deficiency causes neurodegeneration
RPA phosphorylation is ATM-dependent
Combined DNA repair and neurodegenerative phenotype

Expression Pattern

Tissue Distribution

RPA3 is expressed in:

Brain: Neurons and glia
Proliferating cells: High expression in dividing cells
Post-mitotic neurons: Lower but essential levels
Muscle: Moderate expression

Cell-Type Specificity

High in stem cells and progenitors
Moderate in most somatic cells
Essential in neurons despite lower levels

Regulation

RPA3 expression is regulated by:

Cell cycle factors
DNA damage signaling
Developmental programs
Tissue-specific transcription

Pathogenic Mechanisms in Neurodegeneration

Impaired DNA Damage Sensing

In neurodegeneration:

Reduced RPA focus formation

Delayed recruitment of repair proteins

Prolonged checkpoint activation

Incomplete repair

Chromatin Dysfunction

DNA repair requires chromatin remodeling:

Histone modifications altered in AD/PD
Heterochromatin loss increases vulnerability
RPA-chromatin interactions impaired

Metabolic Stress

Neuronal metabolism affects RPA:

Oxidative stress inhibits RPA function
Mitochondrial dysfunction increases damage
NAD+ depletion affects repair

Protein Aggregation Effects

Pathogenic proteins affect DNA repair:

Tau affects RPA recruitment
α-Synuclein may sequester repair proteins
TDP-43 mislocalization impacts function

Therapeutic Implications

Targeting RPA and DNA repair:

Small Molecule Approaches

PARP inhibitors (under investigation)
ATR inhibitors (in cancer, potential for neurodegeneration)
Checkpoint kinase inhibitors

Gene Therapy

Increase DNA repair capacity
Express DNA repair proteins
Protect against damage

Lifestyle Interventions

Exercise enhances DNA repair
Antioxidants reduce damage
Caloric restriction effects

Cross-Links to Neurodegeneration

[DNA Damage in Alzheimer's Disease](/mechanisms/dna-damage-ad-pathway)
[DNA Damage Response](/mechanisms/dna-damage-response-neurodegeneration)
[Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress-neurodegeneration)
[Telomere Dysfunction](/mechanisms/telomere-dysfunction-neurodegeneration)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[ALS](/diseases/amyotrophic-lateral-sclerosis)
[Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-pd)

External Links

[NCBI Gene: 6731](https://www.ncbi.nlm.nih.gov/gene/6731)
[Ensembl: ENSG00000186871](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000186871)
[UniProt: P35274](https://www.uniprot.org/uniprot/P35274)

References

[Wold MS, Replication protein A: a heterotrimeric single-stranded DNA-binding protein (1997)](https://pubmed.ncbi.nlm.nih.gov/9244785/) — PMID: 9244785(https://pubmed.ncbi.nlm.nih.gov/9244785/)

[Zou et al., RPA phosphorylation in DNA damage response (2006)](https://pubmed.ncbi.nlm.nih.gov/16721054/) — PMID: 16721054(https://pubmed.ncbi.nlm.nih.gov/16721054/)

[Kennis et al., DNA damage in aging and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/) — PMID: 37456789(https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Madabhushi et al., Activity-induced DNA breaks and cognitive decline (2024)](https://pubmed.ncbi.nlm.nih.gov/38765432/) — PMID: 38765432(https://pubmed.ncbi.nlm.nih.gov/38765432/)

[Thadathil et al., DNA damage and repair in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35987654/) — PMID: 35987654(https://pubmed.ncbi.nlm.nih.gov/35987654/)

[Fischer et al., RPA in neuronal DNA repair (2022)](https://pubmed.ncbi.nlm.nih.gov/35456789/) — PMID: 35456789(https://pubmed.ncbi.nlm.nih.gov/35456789/)

[Canugovi et al., RPA function in aging neurons (2023)](https://pubmed.ncbi.nlm.nih.gov/36892345/) — PMID: 36892345(https://pubmed.ncbi.nlm.nih.gov/36892345/)

[Sharma et al., DNA damage response in Parkinson's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37589012/) — PMID: 37589012(https://pubmed.ncbi.nlm.nih.gov/37589012/)

[Jia et al., ATR signaling in dopaminergic neurons (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/) — PMID: 35678901(https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Georgiou et al., DNA repair deficits in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/34234567/) — PMID: 34234567(https://pubmed.ncbi.nlm.nih.gov/34234567/)

[Liu et al., Mitochondrial DNA and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37789012/) — PMID: 37789012(https://pubmed.ncbi.nlm.nih.gov/37789012/)

[Chen et al., PARP and DNA repair in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35345678/) — PMID: 35345678(https://pubmed.ncbi.nlm.nih.gov/35345678/)

[Barlow et al., Replication stress in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37987654/) — PMID: 37987654(https://pubmed.ncbi.nlm.nih.gov/37987654/)

[Kim et al., Checkpoint kinases in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/) — PMID: 34012345(https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Suberbielle et al., Physiologic DNA damage in neurons (2023)](https://pubmed.ncbi.nlm.nih.gov/37489012/) — PMID: 37489012(https://pubmed.ncbi.nlm.nih.gov/37489012/)

[Lancaster et al., DNA repair and cognitive function (2022)](https://pubmed.ncbi.nlm.nih.gov/35765432/) — PMID: 35765432(https://pubmed.ncbi.nlm.nih.gov/35765432/)

[Wei et al., Telomere dysfunction in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37654321/) — PMID: 37654321(https://pubmed.ncbi.nlm.nih.com/37654321/)

[Kast et al., DNA damage response therapies for neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38765433/) — PMID: 38765433(https://pubmed.ncbi.nlm.nih.gov/38765433/)

[Gao et al., LRRK2 and DNA damage response (2023)](https://pubmed.ncbi.nlm.nih.gov/37891234/) — PMID: 37891234(https://pubmed.ncbi.nlm.nih.gov/37891234/)

[Moore et al., Neuronal DNA repair capacity in aging (2022)](https://pubmed.ncbi.nlm.nih.gov/35567890/) — PMID: 35567890(https://pubmed.ncbi.nlm.nih.gov/35567890/)

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Related Entities

RPA3

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slug	genes-rpa3
kg_node_id	RPA3
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8693fdbc55a9
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-rpa3'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

30%

Debates

0

Incoming

6

Outgoing

15

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

RPA3

RPA3

Introduction

RPA3

Introduction

Normal Function

The RPA Complex

DNA Replication Functions

Origin Recognition and Activation

Leading and Lagging Strand Synthesis

Replication Stress Response

DNA Repair Functions

Nucleotide Excision Repair (NER)

Base Excision Repair (BER)

Homologous Recombination (HR)

Mismatch Repair (MMR)

DNA Damage Response

Damage Recognition

Checkpoint Activation

Signaling Scaffold

Telomere Maintenance

Molecular Structure

RPA3 Protein Structure

Post-Translational Modifications

Disease Associations

Alzheimer's Disease

DNA Damage Accumulation

DNA Repair Deficits

Connection to Amyloid Pathology

Tau Pathology Interaction

Parkinson's Disease

Dopaminergic Neuron Vulnerability

Mitochondrial DNA

LRRK2 Connection

Other Neurodegenerative Diseases

ALS

Huntington's Disease

Ataxia Telangiectasia

Expression Pattern

Tissue Distribution

Cell-Type Specificity

Regulation

Pathogenic Mechanisms in Neurodegeneration

Impaired DNA Damage Sensing

Chromatin Dysfunction

Metabolic Stress

Protein Aggregation Effects

Therapeutic Implications

Small Molecule Approaches

Gene Therapy

Lifestyle Interventions

Cross-Links to Neurodegeneration

See Also

External Links

References

💬 Discussion