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BAP1

Developmental stage

Expressed in trophoblast stem cells during placenta development (at protein levels) (PubMed:34170818). Decreased expression levels correlate with epithelial-mesenchymal transition (EMT) during trophoblast cell differentiation (at protein level) (PubMed:34170818).

Domain

Possesses 2 overlapping nuclear localization sequences (NLS), a classic bipartite NLS and a non-classical PY-NLS (PubMed:35446349). The classical NLS probably mediates import via the importin alpha/beta system while the PY-NLS mediates nuclear import via the transportin system (PubMed:35446349).

The positively charged C-terminal tail stabilizes the interaction with nucleosomes/chromatosomes through interaction with the DNA backbone (PubMed:30258054, PubMed:36991118). Binding of ASXL1 just upstream of the positively charged C-terminal tail may stabilize its orientation to align the PR-DUB with its H2AK118ub1 substrate (PubMed:36991118).

The ubiquitin C-terminal hydrolase (UCH) domain, together with the DEUBAD domain of ASXL1, forms the ubiquitin binding cleft of the PR-DUB complex.

The positively charged Arg-finger motif mediates interaction with the histone H2A-H2B acidic patch; this interaction is critical for nucleosomal H2AK119ub1 deubiquitination activity but not nucleosomal binding.

Function

Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1 (PubMed:12485996, PubMed:18757409, PubMed:20436459, PubMed:25451922, PubMed:35051358). Catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-120' (H2AK119ub1) (PubMed:20436459, PubMed:25451922, PubMed:30664650, PubMed:35051358). Does not deubiquitinate monoubiquitinated histone H2B (PubMed:20436459, PubMed:30664650). The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability (PubMed:20805357, PubMed:30664650, PubMed:36180891). Antagonizes PRC1 mediated H2AK119ub1 monoubiquitination (PubMed:30664650). As part of the PR-DUB complex, associates with chromatin enriched in histone marks H3K4me1, H3K4me3, and H3K27Ac, but not in H3K27me3 (PubMed:36180891). Recruited to specific gene-regulatory regions by YY1 (PubMed:20805357). Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains (PubMed:19188440, PubMed:19815555). Deubiquitination of HCFC1 does not lead to increase stability of HCFC1 (PubMed:19188440, PubMed:19815555). Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination (PubMed:19117993). It however does not mediate deubiquitination of BRCA1 and BARD1 (PubMed:19117993). Able to mediate autodeubiquitination via intramolecular interactions to counteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration (PubMed:24703950). Negatively regulates epithelial-mesenchymal transition (EMT) of trophoblast stem cells during placental development by regulating genes involved in epithelial cell integrity, cell adhesion and cytoskeletal organization (PubMed:34170818).

Involvement in disease

Mesothelioma, malignant

MESOM

An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.

None

The gene represented in this entry is involved in disease pathogenesis.

Tumor predisposition syndrome 1

TPDS1

An autosomal dominant condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma.

None

The disease is caused by variants affecting the gene represented in this entry.

Melanoma, uveal, 2

UVM2

Most common intraocular malignancy, arising from melanocytes in the iris, ciliary body, or choroid. Metastases develop in more than 30% of case patients, almost invariably in the liver, with poor prognosis.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Kury-Isidor syndrome

KURIS

An autosomal dominant neurodevelopmental disorder characterized mainly by mild global developmental delay apparent from infancy or early childhood, and behavioral problems, including autism in most patients. Intellectual development may be mildly delayed, borderline, or even normal. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and non-specific dysmorphic facial features.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Ubiquitinated: monoubiquitinated at multiple sites within its nuclear localization signal (NLS) BY UBE2O, leading to cytoplasmic retention (PubMed:24703950). Able to mediate autodeubiquitination via intramolecular interactions to counteract cytoplasmic retention (PubMed:24703950). Monoubiquitinated on at least 4 sites near or within its PY-NLS (PubMed:35446349).

Sequence Similarities

Belongs to the peptidase C12 family. BAP1 subfamily.

Tissue Specificity

Highly expressed in testis, placenta and ovary (PubMed:9528852). Expressed in breast (PubMed:9528852). levels in the placenta increase over the course of pregnancy (PubMed:34170818).

Cellular localization

Alternative names

KIAA0272, hucep-6, BAP1, Ubiquitin carboxyl-terminal hydrolase BAP1, BRCA1-associated protein 1, Cerebral protein 6

swissprot:Q92560 omim:603089 entrezGene:8314

Other research areas