BAP1 (BRCA1-Associated Protein 1)

BAP1 (BRCA1-Associated Protein 1)

<div class="infobox infobox-gene">
<h3>BAP1</h3>
<table> [@zhang2018]
<tr><td><strong>Full Name</strong></td><td>BRCA1-Associated Protein 1</td></tr> [@carbone2020]
<tr><td><strong>Gene Symbol</strong></td><td>BAP1</td></tr> [@nithianantham2021]
<tr><td><strong>Chromosomal Location</strong></td><td>3p21.1</td></tr> [@madabhushi2015]
<tr><td><strong>NCBI Gene ID</strong></td><td>[8314](https://www.ncbi.nlm.nih.gov/gene/8314)</td></tr> [@von2016]
<tr><td><strong>OMIM</strong></td><td>[603089](https://omim.org/entry/603089)</td></tr> [@wenderski2023]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000163930](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163930)</td></tr> [@machida2009]
<tr><td><strong>UniProt</strong></td><td>[Q92560](https://www.uniprot.org/uniprot/Q92560)</td></tr> [@lee2023]
<tr><td><strong>Protein</strong></td><td>Ubiquitin carboxyl-terminal hydrolase BAP1</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), BAP1 tumor predisposition syndrome, neurodegeneration</td></tr>
</table>
</div>

Overview

BAP1 (BRCA1-Associated Protein 1)

<div class="infobox infobox-gene">
<h3>BAP1</h3>
<table> [@zhang2018]
<tr><td><strong>Full Name</strong></td><td>BRCA1-Associated Protein 1</td></tr> [@carbone2020]
<tr><td><strong>Gene Symbol</strong></td><td>BAP1</td></tr> [@nithianantham2021]
<tr><td><strong>Chromosomal Location</strong></td><td>3p21.1</td></tr> [@madabhushi2015]
<tr><td><strong>NCBI Gene ID</strong></td><td>[8314](https://www.ncbi.nlm.nih.gov/gene/8314)</td></tr> [@von2016]
<tr><td><strong>OMIM</strong></td><td>[603089](https://omim.org/entry/603089)</td></tr> [@wenderski2023]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000163930](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163930)</td></tr> [@machida2009]
<tr><td><strong>UniProt</strong></td><td>[Q92560](https://www.uniprot.org/uniprot/Q92560)</td></tr> [@lee2023]
<tr><td><strong>Protein</strong></td><td>Ubiquitin carboxyl-terminal hydrolase BAP1</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), BAP1 tumor predisposition syndrome, neurodegeneration</td></tr>
</table>
</div>

Overview

BRCA1 is a human gene. Variants in BRCA1 have been implicated in Neurodegeneration and BAP1 Deficiency, Alzheimer's Disease, Parkinson's Disease. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Function

BAP1 encodes a nuclear deubiquitinase (DUB) of the ubiquitin C-terminal hydrolase (UCH) family that plays essential roles in chromatin regulation, DNA damage response, and cell fate determination. BAP1 is the catalytic subunit of the Polycomb Repressive Deubiquitinase (PR-DUB) complex, which removes monoubiquitin from histone H2A at lysine 119 (H2AK119ub1) — a mark placed by the [Polycomb Repressive Complex 1 (PRC1)](/mechanisms/polycomb-regulation).

BAP1 functions through several key mechanisms:

• H2AK119 deubiquitination: As part of the PR-DUB complex (with ASXL1/2/3), BAP1 removes PRC1-deposited ubiquitin marks from H2A, counteracting Polycomb-mediated gene silencing and enabling transcription of developmental and differentiation genes
• DNA damage response: BAP1 is rapidly recruited to DNA double-strand breaks where it deubiquitinates H2AK119 to facilitate homologous recombination repair and checkpoint activation
• Metabolic regulation: BAP1 regulates calcium signaling through the IP3 receptor, linking chromatin remodeling to cellular metabolic state
• Cell death regulation: BAP1 promotes [ferroptosis](/entities/ferroptosis) by repressing SLC7A11 (the cystine/glutamate antiporter), thereby modulating oxidative stress sensitivity

Disease Associations

Neurodegeneration and BAP1 Deficiency

• Progressive neurodegeneration with cortical and hippocampal neuronal loss
• Accumulation of H2AK119ub1, leading to widespread transcriptional silencing of neuronal genes
• Mitochondrial dysfunction through impaired expression of electron transport chain components
• Enhanced oxidative stress due to dysregulated [NRF2](/genes/nfe2l2) target genes

Alzheimer's Disease

• Excessive Polycomb-mediated silencing of synaptic and plasticity genes, contributing to synaptic loss
• Impaired DNA damage repair in postmitotic [neurons](/entities/neurons), accelerating genomic instability associated with AD
• Dysregulated [tau](/genes/mapt) phosphorylation — BAP1 normally maintains expression of phosphatase genes ([PP2A](/genes/ppp2ca)) that dephosphorylate [tau](/proteins/tau)
• Increased ferroptosis vulnerability in neurons due to SLC7A11 repression, consistent with oxidative damage patterns in AD brain

Parkinson's Disease

• BAP1-dependent chromatin remodeling is required for maintaining dopaminergic gene expression programs
• BAP1 interacts with [PARKIN](/genes/prkn) in the DNA damage response pathway — PARKIN ubiquitinates nuclear substrates that BAP1 can deubiquitinate, creating a regulatory circuit
• Loss of BAP1 activity sensitizes neurons to mitochondrial stress and [α-synuclein](/proteins/alpha-synuclein) toxicity
• BAP1 deficiency impairs mitophagy through disrupted [PINK1](/genes/pink1)-dependent signaling

BAP1 Tumor Predisposition Syndrome

Expression Profile

BAP1 is ubiquitously expressed but shows enrichment in specific brain regions:

• Cerebral cortex — High expression in neurons of layers II/III and V, particularly in prefrontal and temporal cortex
• Hippocampus — Strong expression in CA1 and CA3 pyramidal neurons and dentate gyrus granule cells
• Cerebellum — Enriched in Purkinje cells
• Substantia nigra — Expressed in tyrosine hydroxylase-positive dopaminergic neurons
• Hypothalamus — Moderate expression, relevant to metabolic regulation

Common Variants and Risk Alleles

| Variant | Type | Association | Effect |
|---------|------|-------------|--------|
| rs11550487 | Missense | Cancer predisposition | Reduced DUB activity |
| rs147162025 | Regulatory | Cognitive decline risk (suggestive) | Altered BAP1 expression in brain |
| c.122+1G>A | Splice site | BAP1-TPDS | Exon skipping, truncated protein |
| p.C91S | Missense | BAP1-TPDS | Catalytic site disruption |

Therapeutic Implications

• [HDAC](/entities/hdac-enzymes) inhibitors: Can partially compensate for H2AK119ub1 accumulation caused by BAP1 loss, as [HDAC](/genes/hdac1) inhibition promotes alternative chromatin opening mechanisms
• EZH2 inhibitors: Reducing [PRC2](/genes/ezh2)-mediated H3K27 methylation may compensate for excessive Polycomb activity when BAP1 is deficient
• Ferroptosis inhibitors: Given BAP1's role in promoting ferroptosis via SLC7A11, ferroptosis inhibitors (liproxstatin-1, ferrostatin-1) may protect neurons with BAP1 dysfunction
• Ubiquitin-proteasome modulators: Enhancing BAP1 protein stability could restore deubiquitinase function in aging neurons

See Also

• [EZH2](/genes/ezh2) — Polycomb methyltransferase, functionally opposes BAP1
• [PRKN](/genes/prkn) — Parkin E3 ligase, interacts with BAP1 in DDR
• [Chromatin Remodeling in Neurodegeneration](/mechanisms/chromatin-remodeling)
• [USP7](/genes/usp7) — Related deubiquitinase in neurodegeneration
• [HDAC1](/genes/hdac1) — Histone deacetylase, alternative epigenetic target

External Links

• [NCBI Gene: BAP1](https://www.ncbi.nlm.nih.gov/gene/8314)
• [GeneCards: BAP1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=BAP1)
• [Allen Brain Atlas: BAP1](https://human.brain-map.org/microarray/search/show?search_term=BAP1)
• [OMIM: 603089](https://omim.org/entry/603089)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving BAP1 (BRCA1-Associated Protein 1) discovered through SciDEX knowledge graph analysis: