BAP1: Proteins and Enzymes

Breast Cancer 1 (BRCA1) Associated Protein-1 (BAP1) is a deubiquitinating enzyme that was identified in a screen for proteins that interact with BRCA1. The human protein has a predicted molecular weight of 81 kDa and shares 93% and 92% amino acid (aa) sequence identity with the mouse and rat orthologs, respectively. BAP1 has two functional domains, an N-terminal Ubiquitin C-terminal Hydrolase (UCH) domain and a C-terminal BRCA1-interacting domain. The UCH domain contains an active site cysteine residue, Cys91 in humans, which catalyzes the hydrolysis of Ubiquitin isopeptide bonds. BAP1 also contains two consensus nuclear localization sequences, NLS1, from aa 656-661, and NLS2, from aa 717-722. NLS2, but not NLS1, is required for the nuclear localization of BAP1. BAP1 forms a ternary complex with Host Cell Factor 1 (HCF-1) and YY1 and regulates the expression of several genes. Deubiquitination of HCF-1 by BAP1 was reported to be required for efficient G1/S phase transition, suggesting that BAP1 may be involved in cell cycle regulation. Accumulating evidence indicates that BAP1 also acts as a tumor suppressor. For instance, inactivation or loss of BAP1 is associated with several types of cancer, including myelodysplastic syndrome, melanoma, renal cell carcinoma, and malignant mesothelioma.