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| Full Name | BRCA1-Associated Protein 1 |
| Gene Symbol | BAP1 |
| Chromosomal Location | 3p21.1 |
| NCBI Gene ID | [8314](https://www.ncbi.nlm.nih.gov/gene/8314) |
| OMIM | [603089](https://omim.org/entry/603089) |
| Ensembl | [ENSG00000163930](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163930) |
| UniProt | [Q92560](https://www.uniprot.org/uniprot/Q92560) |
| Protein | Ubiquitin carboxyl-terminal hydrolase BAP1 |
| Associated Diseases | [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), BAP1 tumor predisposition syndrome, neurodegeneration |
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.
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).
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 by repressing SLC7A11 (the cystine/glutamate antiporter), thereby modulating oxidative stress sensitivity
BAP1 interacts physically with BRCA1, host cell factor 1 (HCF-1), FOXK1/K2, and the transcription factor YY1, forming distinct functional complexes in the nucleus.
¶ Neurodegeneration and BAP1 Deficiency
Emerging research has identified BAP1 as a critical regulator of neuronal survival and homeostasis. BAP1 conditional knockout in mouse brain causes:
- 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 target genes
BAP1 levels are reduced in AD cortex and hippocampus. The consequences include:
- Excessive Polycomb-mediated silencing of synaptic and plasticity genes, contributing to synaptic loss
- Impaired DNA damage repair in postmitotic neurons, accelerating genomic instability associated with AD
- Dysregulated tau phosphorylation — BAP1 normally maintains expression of phosphatase genes (PP2A) that dephosphorylate tau
- Increased ferroptosis vulnerability in neurons due to SLC7A11 repression, consistent with oxidative damage patterns in AD brain
BAP1 also deubiquitinates and stabilizes several transcription factors required for neuronal survival, including p53 family members.
In PD substantia nigra dopaminergic neurons:
- BAP1-dependent chromatin remodeling is required for maintaining dopaminergic gene expression programs
- BAP1 interacts with PARKIN 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 toxicity
- BAP1 deficiency impairs mitophagy through disrupted PINK1-dependent signaling
Germline BAP1 mutations cause BAP1-TPDS (OMIM 614327), predisposing to mesothelioma, uveal melanoma, renal cell carcinoma, and cutaneous melanocytic tumors. While primarily a cancer syndrome, BAP1-TPDS carriers show subtle neurocognitive phenotypes including reduced cognitive flexibility and processing speed, suggesting subclinical neuronal effects.
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
Expression is predominantly nuclear, consistent with BAP1's role in chromatin regulation. BAP1 protein levels decline with normal aging, with accelerated loss in neurodegenerative conditions.
¶ 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 |
- HDAC inhibitors: Can partially compensate for H2AK119ub1 accumulation caused by BAP1 loss, as HDAC inhibition promotes alternative chromatin opening mechanisms
- EZH2 inhibitors: Reducing PRC2-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