Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al. 2009). The deubiquitylating - or deubiquitinating - enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin dependent signalling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubi-quitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell sig-nalling events (Komander et al. 2009). There are two main classes of DUB, cysteine proteases and metallo-proteases. BRCA1 Associated Protein 1 (BAP1) is a cysteine protease and member of the UCH family of ubiquitin C-terminal hydrolases. Cloning of the human BAP1 gene was first described by Jensen et al. (1998). The nuclear DUB BAP1 is a tumour suppressor deleted and mutated in an increasing number of cancers of diverse origins thereby making BAP1 the most frequently and widely mutated DUB-encoding gene in cancer (Daou et al. 2015). BAP1 contains binding domains for BRCA1 (Breast cancer type 1) and BARD1 (BRCA1-associated RING domain protein 1), which form a tumour suppressor heterodimeric complex, and HCFC1 (Host cell factor 1), which interacts with histone-modifying complexes during cell division. BAP1 also interacts with ASXL1 (Putative Polycomb group protein) to form the Polycomb group repressive de-ubiquitylase complex (PR-DUB), which is involved in stem cell pluripotency and other developmental processes (Harbour et al. 2010). More BAP1 has been recently,identified as a DUB for Krüppel-like zinc-finger transcription factor 5 (KLF5), a transcription factor that is highly expressed in certain types of breast cancers. KLF5 has been identified as an unstable protein that is ubiquitylated by WWP1 (NEDD4-like E3 ligase), SCFFBW7 (a SKP1–cullin-1–F-box complex that contains FBW7 as the F-box protein) and Smurf2 (SMAD Specific E3 ligase 2)and degraded. BAP1 promotesbreast cancer cell proliferation andmigration in vitro and tumourgrowth and lung metastasis in vivo.The results from this study suggest thatBAP1 and KLF5 are potentialtherapeutic targets for breast cancer (Qin et al. 2015). Alternate names:
- BRCA1 Associated Protein 1
- BRCA1 Associated Protein-1 (Ubiquitin Carboxy-Terminal Hydrolase)
- Cerebral Protein 6
- Ubiquitin Carboxy-Terminal Hydrolase 2
- BRCA1-Associated Protein 1
- Cerebral Protein-13
Daou S, et al. (2015) The BAP1/ASXL2 histone H2A deubiquitinase complex regulates cell proliferation and Is disrupted in cancer. The Journal of biological chemistry 290:28643-28663.
- Harbour JW, et al. (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410-1413.
- Jensen DE, et al. (1998) BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16:1097-1112.
- Komander D, et al. (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550-563.
- Qin J, et al. (2015) BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5. Nature communications 6:8471.
- Reyes-Turcu FE et al. (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annual review of biochemistry 78:363-397.