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 H2AK119³⁵. The BAP1-ASXL1 complex (PR-DUB) has H2A-K119ub deubiquitylase activity opposite to PRC1³⁴. OGT contributes to the fine tuning of these epigenetic marks via O-GlcNacylation of PHCs⁴⁰. 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 YY1³⁹ or HCF1 and OGT⁴¹. 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 biogenesis⁴².

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.