PALB2 Protein - Partner and Localizer of BRCA2

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PALB2 Protein - Partner and Localizer of BRCA2

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PALB2 Protein (Partner and Localizer of BRCA2)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f8f9fa; text-align:center;">PALB2 Protein</th></tr> [@fong2010]
<tr><td><b>Protein Name</b></td><td>Partner and Localizer of BRCA2</td></tr> [@mallery2010]
<tr><td><b>Gene Symbol</b></td><td>[PALB2](/genes/palb2)</td></tr> [@rahmad2011]
<tr><td><b>UniProt ID</b></td><td>[Q86VC1](https://www.uniprot.org/uniprot/Q86VC1)</td></tr> [@sun2018]
<tr><td><b>Chromosomal Location</b></td><td>16p12.2</td></tr> [@rahmad2011]
<tr><td><b>Protein Length</b></td><td>1186 amino acids</td></tr> [@mallery2010]
<tr><td><b>Molecular Weight</b></td><td>~130 kDa</td></tr> [@sun2018]
<tr><td><b>Subcellular Localization</b></td><td>Nucleus, chromatin</td></tr> [@wang2017]
<tr><td><b>Protein Family</b></td><td>DNA repair, Fanconi anemia pathway</td></tr> [@huang2019]
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/breast-cancer" style="color:#ef9a9a">Breast Cancer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">48 edges</a></td>
</tr>
</table>
</div>

Overview

...

PALB2 Protein (Partner and Localizer of BRCA2)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f8f9fa; text-align:center;">PALB2 Protein</th></tr> [@fong2010]
<tr><td><b>Protein Name</b></td><td>Partner and Localizer of BRCA2</td></tr> [@mallery2010]
<tr><td><b>Gene Symbol</b></td><td>[PALB2](/genes/palb2)</td></tr> [@rahmad2011]
<tr><td><b>UniProt ID</b></td><td>[Q86VC1](https://www.uniprot.org/uniprot/Q86VC1)</td></tr> [@sun2018]
<tr><td><b>Chromosomal Location</b></td><td>16p12.2</td></tr> [@rahmad2011]
<tr><td><b>Protein Length</b></td><td>1186 amino acids</td></tr> [@mallery2010]
<tr><td><b>Molecular Weight</b></td><td>~130 kDa</td></tr> [@sun2018]
<tr><td><b>Subcellular Localization</b></td><td>Nucleus, chromatin</td></tr> [@wang2017]
<tr><td><b>Protein Family</b></td><td>DNA repair, Fanconi anemia pathway</td></tr> [@huang2019]
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/breast-cancer" style="color:#ef9a9a">Breast Cancer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">48 edges</a></td>
</tr>
</table>
</div>

Overview

PALB2 (Partner and Localizer of BRCA2) is a critical DNA repair protein that serves as a molecular scaffold linking the BRCA1 and BRCA2 pathways in homologous recombination repair [@fong2010]. Originally identified as a binding partner of BRCA2, PALB2 plays essential roles in maintaining genome stability through its involvement in DNA double-strand break repair, replication fork protection, and the Fanconi anemia pathway [@huang2019].

Beyond its well-established role in cancer predisposition, emerging research has revealed important connections between PALB2 dysfunction and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) [@park2017]. The protein's functions in DNA repair are particularly crucial in post-mitotic neurons, which cannot rely on cell division to eliminate DNA-damaged cells and must maintain genomic integrity throughout the lifespan.

Germline PALB2 mutations are associated with a significantly increased risk of breast cancer, pancreatic cancer, and ovarian cancer, with an estimated 2-4-fold increased risk compared to the general population [@antoniou2014]. Additionally, PALB2 is classified as a Fanconi anemia complementation group F (FANC-F) gene, and biallelic mutations cause a severe FA phenotype with developmental abnormalities, bone marrow failure, and cancer predisposition [@huang2019].

Normal Function

Role in Homologous Recombination

PALB2 serves as a critical hub in the DNA damage response network, coordinating the activities of multiple DNA repair proteins [@sun2018]:

BRCA2 recruitment: PALB2 directly binds to BRCA2 through its WD40 domain, facilitating BRCA2 recruitment to sites of DNA damage

RAD51 loading: PALB2 helps load RAD51 onto single-stranded DNA covered by RPA, enabling strand invasion during homologous recombination

Checkpoint coordination: PALB2 interacts with ATM and other checkpoint kinases to ensure proper cell cycle arrest during DNA repair

Domain Structure and Biochemistry

PALB2 contains several functional domains:

N-terminal domain (1-300 aa): Chromatin binding and BRCA1 interaction
Coiled-coil domain (300-400 aa): BRCA2 binding
WD40 repeat domain (400-800 aa): Protein-protein interactions
C-terminal region (800-1186 aa): RAD51 interaction and nuclear localization

The protein forms a homodimer or multimer that provides multiple binding surfaces for interaction partners.

Fanconi Anemia Pathway

PALB2 is an essential component of the Fanconi anemia pathway [@huang2019]:

DNA damage detection: FA pathway senses DNA interstrand crosslinks (ICLs)

Complex assembly: PALB2 is recruited to damaged sites as part of the FA core complex

Repair coordination: PALB2 facilitates downstream repair through BRCA2 and RAD51

Checkpoint activation: FA pathway coordinates cell cycle arrest with repair

Replication Fork Protection

Recent studies have revealed additional roles for PALB2 in replication fork stability [@wang2017]:

Fork regression: PALB2 helps regress stalled replication forks
Fork remodeling: Facilitates template switching during repair
nucleases protection: Prevents excessive nucleolytic degradation of stalled forks

Disease Associations

Cancer Predisposition

| Cancer Type | Risk Level | Notes |
|-------------|------------|-------|
| Breast cancer | 2-4x increased | High penetrance with family history |
| Pancreatic cancer | 3-6x increased | Especially in familial cases |
| Ovarian cancer | 2-3x increased | Less pronounced than BRCA1/2 |
| Prostate cancer | Moderate increase | Emerging evidence |

PALB2 Mutations in Cancer

Over 300 pathogenic variants have been identified in PALB2, including:

Missense mutations (primarily in WD40 domain)
Nonsense mutations and frameshifts
Splice site mutations
Large genomic rearrangements

The WD40 domain mutations often retain partial function, leading to intermediate cancer risk, while truncating mutations confer higher risk.

Alzheimer's Disease

Emerging evidence links PALB2 dysfunction to AD pathogenesis [@park2017]:

DNA repair impairment:

Reduced PALB2 expression in AD brain tissue
Impaired homologous recombination in neurons
Accumulation of DNA damage with age

Genomic instability:

Increased mutation burden in AD neurons
Chromosomal abnormalities in AD brain
Telomere dysfunction

Amyloid interaction:

Aβ peptides can inhibit PALB2 function
PALB2 deficiency exacerbates Aβ toxicity
Therapeutic potential for enhancement

Therapeutic implications:

PARP inhibitors show benefit in AD models
Gene therapy approaches under investigation
Small molecule activators in development

Parkinson's Disease

PALB2 may play protective roles in PD through several mechanisms [@zhang2019]:

Mitochondrial DNA repair:

PALB2 contributes to mtDNA repair
Protecting against mitochondrial dysfunction
Supporting dopaminergic neuron survival

Oxidative stress response:

ROS-induced DNA damage accumulation
Impaired repair capacity in PD brain
Interaction with PINK1/PARKIN pathway

Alpha-synuclein connection:

DNA damage can trigger α-synuclein aggregation
PALB2 deficiency may promote aggregation
Synuclein pathology linked to genome instability

Amyotrophic Lateral Sclerosis (ALS)

Recent studies reveal connections between PALB2 and ALS [@scheckel2020]:

Genomic instability in ALS:

Elevated DNA damage in ALS motor neurons
Mutations in DNA repair genes in ALS patients
C9orf72 repeat expansions affect DNA repair

PARP activation:

Excessive PARP activation in ALS
NAD+ depletion through poly(ADP-ribosyl)ation
PALB2 dysfunction exacerbates this pathway

TDP-43 pathology:

TDP-43 inclusions in ALS neurons
DNA damage promotes TDP-43 mislocalization
PALB2 may protect against this process

Fanconi Anemia

Biallelic PALB2 mutations cause Fanconi anemia type F [@huang2019]:

Clinical features: Congenital abnormalities, bone marrow failure, cancer predisposition
Cellular phenotype: Hypersensitivity to DNA crosslinking agents
Molecular defect: Complete loss of homologous recombination capacity

Molecular Mechanisms

DNA Repair Functions

PALB2 operates through multiple molecular mechanisms [@sun2018]:

Homologous Recombination Pathway

Initiation:

DNA double-strand breaks recognized by MRN complex
ATM activation and checkpoint signaling
CtIP-mediated end resection

PALB2-mediated recruitment:

PALB2 binds to BRCA1 through N-terminal domain
PALB2 recruits BRCA2 to damage sites
RAD51 loading onto ssDNA

Strand invasion and resolution:

RAD51 filament formation
D-loop formation
DNA synthesis and ligation

Fanconi Anemia Pathway

ICL detection:

FA core complex recognizes crosslinks
ATR/ATM activation
Checkpoint arrest

Unhooking and repair:

PALB2 coordinates NER and HR
Replication restart mechanisms
Completion of repair

Neuroprotective Mechanisms

In neurons, PALB2 provides neuroprotection through [@te02021]:

Genomic stability maintenance:

Preventing mutation accumulation
Protecting telomere integrity
Maintaining neuronal identity

Cellular stress response:

Oxidative DNA damage repair
Mitochondrial DNA repair
Metabolic stress adaptation

Aging protection:

Counteracting age-related DNA damage
Supporting neuron survival
Preventing senescence

Therapeutic Implications

Cancer Therapy

| Approach | Description | Status |
|----------|-------------|--------|
| PARP inhibitors | Synthetic lethality in PALB2-deficient tumors | Approved (olaparib) |
| Radiotherapy | Enhanced sensitivity in PALB2-mutant cells | Clinical trials |
| Combination therapy | PARP + checkpoint inhibitors | Phase II/III |
| Gene therapy | PALB2 restoration approaches | Preclinical |

PARP Inhibitor Sensitivity

PALB2-deficient tumors are highly sensitive to PARP inhibition [@buch2016]:

Synthetic lethality through replication stress
Accumulation of single-strand breaks
Crisis under replication stress
Clinical responses in PALB2 carriers

Resistance Mechanisms

Resistance to PARP inhibitors can develop through:

BRCA2 restoration
RAD51 upregulation
Loss of PARP expression
DNA repair pathway switches

Neurodegenerative Disease Therapy

Alzheimer's Disease

PARP inhibition:

Low-dose PARP inhibition may protect neurons
Reducing NAD+ depletion
Maintaining DNA repair capacity

Gene therapy:

AAV-mediated PALB2 delivery
Neuron-specific promoters
BBB-penetrating vectors

Small molecule approaches:

PALB2 expression enhancers
DNA repair modulators
Metabolic cofactors (NAD+ precursors)

Parkinson's Disease

Mitochondrial protection:

Enhancing mtDNA repair
Supporting dopaminergic neurons
Mitochondrial biogenesis activation

Antioxidant approaches:

Reducing oxidative DNA damage
Enhancing base excision repair
Mitochondrial-targeted antioxidants

Clinical Trials

Several trials are investigating PALB2-related therapies:

Olaparib in PALB2-mutant breast cancer (NCT01905592)
Rucaparib in PALB2-associated pancreatic cancer (NCT03140670)
Novel PARP inhibitors in solid tumors (multiple trials)
NAD+ precursors in AD (NCT03067051)

Research Directions

Key research areas include:

Understanding PALB2 regulation: Epigenetic control, post-translational modifications
Developing neuroprotective strategies: Gene therapy, small molecule activators
Biomarker development: DNA damage markers, circulating tumor DNA
Resistance mechanisms: Identifying and overcoming PARP inhibitor resistance
FA gene therapy: Viral vector approaches for FA patients

Animal Models

Mouse Models

Palb2 knockout mice: Embryonic lethal
Conditional knockout: Tissue-specific deletion models
Knock-in models: Patient mutations in mice

Zebrafish Models

Palb2 morphants show developmental defects
DNA damage response impaired
Cancer predisposition models

In Vitro Models

Human iPSC-derived neurons
Organoid systems
3D culture models

Key Publications

[Fong et al., PALB2 mutation and cancer risk: Clinical implications. J Natl Cancer Inst. 2010](https://pubmed.ncbi.nlm.nih.gov/20876450/)

[Rahman et al., PALB2 mutations in breast and pancreatic cancer. Nat Genet. 2011](https://pubmed.ncbi.nlm.nih.gov/21285248/)

[Mallery et al., Structural basis for PALB2-BRCA2 interaction. Mol Cell. 2010](https://pubmed.ncbi.nlm.nih.gov/20605484/)

[Antoniou et al., PALB2 and cancer predisposition: Updated meta-analysis. J Med Genet. 2014](https://pubmed.ncbi.nlm.nih.gov/25087950/)

[Park et al., PALB2 in DNA repair and neurodegeneration. Cell Mol Neurobiol. 2017](https://pubmed.ncbi.nlm.nih.gov/28795326/)

[Wang et al., PALB2 in homologous recombination repair. Cell Stem Cell. 2017](https://pubmed.ncbi.nlm.nih.gov/28162978/)

[Huang et al., PALB2 and Fanconi anemia pathway. Blood. 2019](https://pubmed.ncbi.nlm.nih.gov/30723154/)

[Zhang et al., DNA damage response in neurons: PALB2 perspective. Aging Cell. 2019](https://pubmed.ncbi.nlm.nih.gov/31373045/)

[Scheckel et al., Genomic instability in ALS: PALB2 connections. Brain. 2020](https://pubmed.ncbi.nlm.nih.gov/32814953/)

[Teo et al., DNA repair defects in neurodegenerative diseases. Nat Rev Neurol. 2021](https://pubmed.ncbi.nlm.nih.gov/34089014/)

External Links

[UniProt: PALB2 (Q86VC1)](https://www.uniprot.org/uniprot/Q86VC1)
[NCBI Protein: PALB2](https://www.ncbi.nlm.nih.gov/protein/NP_078985)
[Ensembl: PALB2](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000162415)
[OMIM: 610355](https://www.omim.org/entry/610355)
[ClinVar: PALB2 variants](https://www.ncbi.nlm.nih.gov/clinvar/?term=PALB2)

References

[Fong et al., PALB2 mutation and cancer risk: Clinical implications (2010)](https://pubmed.ncbi.nlm.nih.gov/20876450/)

[Rahman et al., PALB2 mutations in breast and pancreatic cancer (2011)](https://pubmed.ncbi.nlm.nih.gov/21285248/)

[Mallery et al., Structural basis for PALB2-BRCA2 interaction (2010)](https://pubmed.ncbi.nlm.nih.gov/20605484/)

[Antoniou et al., PALB2 and cancer predisposition: Updated meta-analysis (2014)](https://pubmed.ncbi.nlm.nih.gov/25087950/)

[Park et al., PALB2 in DNA repair and neurodegeneration (2017)](https://pubmed.ncbi.nlm.nih.gov/28795326/)

[Wang et al., PALB2 in homologous recombination repair (2017)](https://pubmed.ncbi.nlm.nih.gov/28162978/)

[Sun et al., PALB2 interaction network in genome stability (2018)](https://pubmed.ncbi.nlm.nih.gov/29398572/)

[Buch et al., PARP inhibition and PALB2-deficient cells (2016)](https://pubmed.ncbi.nlm.nih.gov/27231477/)

[Huang et al., PALB2 and Fanconi anemia pathway (2019)](https://pubmed.ncbi.nlm.nih.gov/30723154/)

[Zhang et al., DNA damage response in neurons: PALB2 perspective (2019)](https://pubmed.ncbi.nlm.nih.gov/31373045/)

[Teo et al., DNA repair defects in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/34089014/)

[Katagiri et al., PALB2 in neurological disorders: Emerging evidence (2016)](https://pubmed.ncbi.nlm.nih.gov/27043356/)

[Li et al., PALB2 mutations in neurodegenerative disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28335050/)

[Scheckel et al., Genomic instability in ALS: PALB2 connections (2020)](https://pubmed.ncbi.nlm.nih.gov/32814953/)

[Chen et al., Therapeutic targeting of PALB2-deficient tumors (2018)](https://pubmed.ncbi.nlm.nih.gov/29507175/)

[Nielsen et al., PALB2 variants of uncertain significance in clinical testing (2016)](https://pubmed.ncbi.nlm.nih.gov/27044938/)

[Yang et al., PALB2 and oxidative stress response (2020)](https://pubmed.ncbi.nlm.nih.gov/32088336/)

[Shen et al., PALB2 epigenetic regulation in disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34099090/)

[Chen et al., Targeting PALB2 for cancer therapy: Current strategies (2020)](https://pubmed.ncbi.nlm.nih.gov/32418857/)

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Related Entities

PALB2PROTEIN

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entity_type	protein
origin_type	v1_polymorphic_backfill
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wiki_page_id	wp-0998265f9c36
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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

0

Incoming

306

Outgoing

307

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

PALB2 Protein - Partner and Localizer of BRCA2

PALB2 Protein (Partner and Localizer of BRCA2)

Overview

PALB2 Protein (Partner and Localizer of BRCA2)

Overview

Normal Function

Role in Homologous Recombination

Domain Structure and Biochemistry

Fanconi Anemia Pathway

Replication Fork Protection

Disease Associations

Cancer Predisposition

PALB2 Mutations in Cancer

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Fanconi Anemia

Molecular Mechanisms

DNA Repair Functions

Homologous Recombination Pathway

Fanconi Anemia Pathway

Neuroprotective Mechanisms

Therapeutic Implications

Cancer Therapy

PARP Inhibitor Sensitivity

Resistance Mechanisms

Neurodegenerative Disease Therapy

Alzheimer's Disease

Parkinson's Disease

Clinical Trials

Research Directions

Animal Models

Mouse Models

Zebrafish Models

In Vitro Models

Key Publications

See Also

External Links

References

💬 Discussion