Emerging multifaceted roles of BAP1 complexes in biological processes

Abstract

Histone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex's regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

Fig. 1. Compositions of the Polycomb repressive deubiquitinase PR-DUB (BAP1) complex.

A Domain organization of human BAP1, ASXL1, ASXL2, ASXL3, MBD5, and MBD6 proteins. B Domain organization of human FOXK1, FOXK2, KDM1B, HCF-1, OGT, and YY1 proteins. C Compositions of the Drosophila Calypso/ASX complex and human PR-DUB.1, PR-DUB.2, and PR-DUB.3 BAP1 complexes. D The counts per million (CPM) value for ASXL1/2/3 expression in 1,004 human cell lines.

Fig. 2. BAP1 complex’s function at chromatin.

A Domain organization of human BAP1 and the protein–protein interaction interface between BAP1 and other factors. B The crystal structure of Calypso/DEUBAD of ASX dimer 2:2 complex, modified from PDB: 6CGA. C List of known BAP1 substrates. D The transcriptional regulation machinery comprised of the PRC1 complex, PRC2 complex, BAP1 complex, and MLL3 COMPASS, and the DNA double-strand break repair machinery comprised of ATM, the BAP1 complex, and homologous recombination factors.

Fig. 3. BAP1 complex’s function in metabolism.

In nuclei, BAP1 occupies the promoter region of SLC7A11 gene, and negatively regulates the expression of SLC7A11, which mediates the uptake of extracellular cystine. Loss of BAP1 activates the glutathione biosynthesis, which is utilized by GPX4 to detoxify lipid hydroperoxide and to protect tumor cells from ferroptosis. BAP1 could also function as a deubiquitinase for non-histone substrate PGC-1α, which protects PGC-1α from degradation and promotes gluconeogenesis. In the cytosol, BAP1 is critical for the stability of IP3R3 via deubiquitination, which mediates Ca²⁺ flux to mitochondria by suppressing cell transformation (as well as gatekeeper VDAC) and allowing passage of metabolites, nucleotides, and ions in/out of the mitochondria.

Fig. 4. BAP1 complex mutations in cancer.

A General mutation status of BAP1 and the subunits of BAP1 complex in pan human cancers by cBioPortal database (n = 46697) (https://www.cbioportal.org/). B Mutation frequencies of subunits within the BAP1 complex across various human cancer types as obtained from cBioPortal. C Distribution of all BAP1 mutations that occur within the BAP1 protein-coding region as obtained from St. Jude Cloud PeCan (https://pecan.stjude.cloud/proteinpaint/).