BAP1 and cancer

Abstract

BAP1 is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, including the cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response (DDR). Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome that is characterized, at least in the affected families that have been studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.

Figure 1a. BAP1 protein partners

Putative BAP1 protein partners, identified by co-immunoprecipitation and/or affinity-capture mass spectrometry. Proteins forming the putative BAP1 core complex are shown in blue. Other putative BAP1 partners of hypothetical new complexes are shown in beige^{, ,} . Protein partners shown may vary in different cell types and under different conditions.

Figure 1b. Possible mechanisms of BAP1 function

I) Epigenetic regulation of Polycomb target genes is achieved via the cooperation of multiple protein complexes. The signature of gene silencing mediated by PRC2 is the trimethylation of H3K27. PRC1 can be recruited to H3K27me3 sites and contributes to gene silencing via monoubiquitylation of H2AK119. The BAP1-ASXL1 complex (PR-DUB) has H2A-K119ub deubiquitylase activity opposite to PRC1. OGT contributes to the fine tuning of these epigenetic marks via O-GlcNacylation of PHCs. Hypothesis: PR-DUB might be recruited to Polycomb target genes because of the interaction between BAP1, HCF1 and OGT. II) BAP1 regulates gene transcription via association with other protein partners, e.g. HCF1 and YY1 or HCF1 and OGT. Other putative BAP1 partners are shown in grey. Hypothesis: BAP1, HCF1, YY1 and OGT might also be part of one large protein complex. III) BAP1-HCF1-OGT complex increases the stability of PGC-1α, regulating gluconeogenesis and possibly mitochondrial biogenesis. ASXL1/2, Additional sex combs like 1/2; BAP1, BRCA1-assiciated protein 1; BARD1, BRCA1-associated RING domain protein 1; BRCA1, breast cancer type 1 susceptibility protein; CBXs, mammalian chromobox protein homologues; EZHs, enhancer of zeste homologs; FOXK1/2, Forkhead box protein K1/2; HAT1, Histone acetyltransferase 1; HCF1, Host cell factor 1; KDM1B, lysine (K)-specific demethylase 1B; OGT, UDP-glucose-dependent O-glucosyltransferase; PCLs, Polycomb Like proteins; PGC-1α, Peroxisome proliferator-activated receptor gamma coactivator 1α; PHCs, Polyhomeotic-like proteins; PRC1, Polycomb repressive complex 1; PRC2, Polycomb repressive complex 2; PR-DUB, Polycomb repressive deubiquitinase; RING1, Really interesting new gene 1; RNF2, RING finger protein 2; YY1, Ying-Yang 1.

Figure 2. Schematic representation of BAP1 domains and locations of the reported BAP1 germline mutations

All the germline BAP1 mutations found in families with UVM and mesothelioma encode BAP1 proteins lacking the nuclear localization sequence. Most of them have an intact ubiquitin carboxyl-terminal hydrolase (UCH) domain^{, , , , , , ,} . Ba, BARD1 binding domain; H, HCF-1 binding domain; Br, BRCA1 binding domain; Y, YY1 binding domain; ULD, UCH37-like domain; NLS, nuclear localization signal; Red arrows, germline mutations.