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 Table of Contents  
Year : 2019  |  Volume : 5  |  Issue : 2  |  Page : 25-32

Phosphorylation of BRCA1-associated protein 1 as an important mechanism in the evasion of tumorigenesis: A perspective

1 Gene Regulation Laboratory, National Institute of Immunology, New Delhi, India
2 Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
4 Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Biotechnology, School of Engineering and Technology, Jaipur National University, Jaipur, Rajasthan, India
6 Biochemistry and Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India

Date of Submission10-Feb-2019
Date of Acceptance20-Apr-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Deepak Parashar
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee 53226, Wisconsin
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_1_19

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The human BRCA1-associated protein 1 (BAP1), a deubiquitinase, is a tumor suppressor protein known to be associated with a multicellular complex containing tumor suppressors, thereby coregulating various cellular processes such as DNA repair, gene transcription, cell cycle progression, and phosphorylation. Mutation and inactivation of BAP1 have long been reported in many malignancies and has been deployed in the prognosis of few malignancies. However, the mechanism of BAP1 regulation and its therapeutic significance have not been thoroughly explored. In addition to deubiquitination, BAP1 also responds to DNA damage and can induce cell death via apoptosis, necrosis, and ferroptosis. The mechanistic insight of BAP1-regulation is a complex subject and its thorough understanding would address the enigma of BAP1 mutation in malignancy. There are various tiers of regulation, though still needs to be explored, of BAP1 activity such as epigenetic regulation and posttranslational modification (PTM). Of various PTMs, posttranslational phosphorylation (PTP) has been poorly understood and meekly addressed in the literature. Here, we aim to provide an updated and integrated understanding of the PTP-mediated BAP1 regulation and its plausible role in cancer prevention. Exploring the functional consequence of BAP1 phosphorylation in its deubiquitinating potential might establish a new paradigm for its regulation in maintaining cellular homeostasis and cancer prevention.

Keywords: BRCA1-associated protein 1, cancer, cellular homeostasis, deubiquitinases, posttranslational phosphorylation

How to cite this article:
Sharma GP, Geethadevi A, Mishra J, Anupa G, Jadhav K, Vikramdeo K S, Parashar D. Phosphorylation of BRCA1-associated protein 1 as an important mechanism in the evasion of tumorigenesis: A perspective. Cancer Transl Med 2019;5:25-32

How to cite this URL:
Sharma GP, Geethadevi A, Mishra J, Anupa G, Jadhav K, Vikramdeo K S, Parashar D. Phosphorylation of BRCA1-associated protein 1 as an important mechanism in the evasion of tumorigenesis: A perspective. Cancer Transl Med [serial online] 2019 [cited 2020 Jul 14];5:25-32. Available from: http://www.cancertm.com/text.asp?2019/5/2/25/261825

  Introduction Top

BRCA1-associated protein 1 (BAP1) is a 90 kDa protein with a characteristic ubiquitin carboxy-terminal hydrolase (UCH) domain that imparts BAP1 its deubiquitinating function in cellular machinery.[1] The 729 amino acid long structure of BAP1 comprises N-terminus catalytic domain having UCH activity, a C-terminal UCH37-like domain and a unique linker region.[1] BAP1 is a member of deubiquitinases (DUBs) which cleave ubiquitin or ubiquitin-like proteins and play a central role in ubiquitin signaling by regulating the transcriptional silencing, DNA damage signal amplification, and DNA repair.[2],[3] Approximately 100 human DUBs have been identified, over 90% of which are cysteine-proteases whose catalytic sites contain conserved cysteine (C), histidine (H), and aspartate (D) residues,[4] and remaining DUBs are metalloproteases.[5] DUB activity of BAP1 is attributed to its complex structure composition known as polycomb repressive-DUB (PR-DUB).[6] The biological characterization of PR-DUB complex was first reported in Drosophila melanogaster, and that revealed DUB protein Calypso, the counterpart of human BAP1, and a binding partner additional sex combs (ASXs), the counterpart of human ASXL proteins, as constituents of PR-DUB.[7] Mechanistic insights of Calypso/ASX complex have further provided opportunity in intervening the mechanism-based therapeutics against BAP1/ASXL-related human tumors.[8] Human PR-DUB is composed of BAP1 and one of three regulatory ASX-Like proteins (ASXL1/2/3).[9] BAP1, also a tumor suppressor protein, is mutated/inactivated in various types of cancer.[10] More than 90% malignancies are reported to have a heterozygous mutation in BAP1 (BAP1±) and even healthy persons, showing higher sensitivity to the environmental carcinogens, have been found to carry heterozygous mutation.[11] The coordination between BAP1-mediated modifications and ubiquitin can trigger distinct physiological responses, such as the proteasomal degradation of target proteins, changes in protein localization, and the reorganization of some signaling pathways involving p53, nuclear factor-kappa B, receptor tyrosine kinases, Wnt, transforming growth factor-β, and Akt, has been thoroughly studied.[12],[13]

BAP1 and other DUBs are expressed as active enzymes, and their uncontrolled proteolytic activity is governed by interactions with many molecules, such as binding with ubiquitin, scaffold and adaptor proteins,[14],[15] and proteolytic cleavage.[16] Posttranslational modification (PTM) itself includes different regulatory processes versus monoubiquitination, sumoylation, acetylation, and phosphorylation.[17] Recent reports have revealed that phosphorylated BAP1 is recruited to double-strand DNA break sites and promotes DNA repair by coordinating H2A ubiquitination.[10] BAP1 has been found to play critical roles in the epigenetic modification,[7] transcription regulation,[18] DNA damage response (DDR),[19] and cell death.[20] In the present review, we have summarized recent progress in understanding the regulation of BAP1 in context of its cellular functions in cancer cells. Further, we have focused the known posttranslational phosphorylation (PTP) and their potential effect on BAP1 function in tumor suppression. We also highlight the key questions to provide a platform for future investigations and discussion to fill the lacunae in our knowledge of BAP1 role as a key regulator of various cellular processes.

  BAP1 in Cancer Top

BAP1 is a nuclear DUB which interacts with multiprotein complexes as shown in [Figure 1].[21] These complex formations are mediated by tumor suppressors BRCA1, BRCA1-associated RING domain 1 (BARD1), and chromatin-associated proteins, the host cell factor 1 (HCF-1), thus regulating some significant cellular functions such as transcription, the cell cycle, cellular differentiation, cell death, gluconeogenesis, and the DDR.[11] BAP1 gene is located at chromosome region 3p21 and deletion of this region are frequently reported in many malignancies such as mesothelioma and UVMs uveal melanoma (UM), mesothelioma, renal cell carcinoma (RCC), cholangiocarcinoma, and melanocytic tumors.[22] By binding and deubiquitinating BARD1, BAP1 modulates the E3 ubiquitin ligase activity of BRCA1-BARD1 complex, and this regulates DDR.[11] As shown diagrammatically [Figure 2], the tumor suppressor activity of BAP1 is performed by modulating cell cycle, cellular differentiation, cell death, DDR,[10] transcriptional regulation,[23] chromatin modulation,[24] and gluconeogenesis.[25]
Figure 1: Interaction of BRCA1-associated protein 1 with multiprotein complexes

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Figure 2: Major role of BRCA1-associated protein 1 as a tumor suppressor protein

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BAP1 has a functional classical NLS and that deubiquitinating activity and nuclear localization are both required for its tumor suppressor activity. Primarily, BAP1 is localized to the chromatin and performs its cell growth suppressive functions in association with other nuclear factors.[26] These factors, including HCF-1, Yin Yang 1 (YY1), Forkhead Box Protein K1/2, ASXL1/2, and Chromobox protein homolog 1/3, are transcriptionally regulated by BAP1 via its deubiquitinating potential.[15] For instance, BAP1 deubiquitinates HCF-1, and this association is a prerequisite for growth inhibition in RCC cell line.[27] Moreover, an association of BAP1/ASXL1 complex has been shown to help deubiquitin histone H2A in human and mouse cancer cell lines.[24] It has been shown recently that monoubiquitination of the DEUBAD domain of ASXL by BAP1 stabilizes ASXL which in turn promotes BAP1 DUB activity required for tumor suppression function.[28] Further understanding of H2A deubiquitination by BAP1, as shown by Sahtoe et al., has suggested that apart from DEUBAD domain-mediated BAP1 activation, BAP1 C-terminal domain (CTD) is indispensable for the recruitment of BAP1 to nucleosomes and deubiquitination of H2A K119.[9] Exceptionally, studies suggest that BAP1 does not appear to function in the deubiquitination of the BRCA1/BARD1 complex.[29] BAP1 acts as a cell-cycle regulator, and this may be one of the mechanisms through which it carries out its tumor suppressor function.

BAP1 has been reported to undergo both germ line and somatic. However, germ line BAP1 mutations pose a serious concern to BAP1 ± individuals exposing them to multiple familial cancers including UM, mesothelioma, cutaneous melanoma, RCC, and others.[11],[30] Such familial cancer is termed as BAP1 cancer predisposition syndrome and has recently been reviewed in UM.[31] Somatic mutations have been reported to be associated with metastases in many cancer,[32],[33] a comparative study of BAP1 germ line versus somatic mutations in UM resulted in critical information about both risk and time of metastasis in an individual.[34] Using multiple databases, Wang et al. carried out a tissue-specific significance of BAP1 mutation in prognostic prediction among different types of cancer and concluded that the prognostic value of BAP1 is applicable to UM and clear cell RCC (CCRCC), but not to malignant pleural mesothelioma or cholangiocarcinoma.[22] The study may warrant further precise molecular taxonomy to segregate patients into particular subgroups in UM and CCRCC. Recently shown is that ASXL1/2-mediated stabilization of BAP1 is prone to many somatic and germ line mutations of BAP1 as shown in [Table 1].[35] BAP1 deletion leads to the development of immature T and B lymphocytes resulting in a wide range of tumors.[36] BAP1 catalytic activity and its phosphorylation are critical for promoting DNA repair, and cellular recovery from DNA damage as knockdown studies have suggested the downregulation of genes involved in the DNA repair.[10] Hebert et al. demonstrated that BAP1-DUB activity is essential for maintaining cytoskeleton organization, mitochondrial activity, reactive oxygen species management, and augmentation of the EMT pathway.[37] Recent studies have demonstrated extra-nuclear localization of BAP1, in the cytoplasm specifically in the endoplasmic reticulum (ER).[38] ER-localized BAP1-DUBs and stabilizes type 3 inositol-1, 4, 5-trisphosphate receptor (IP3R3) and regulates intracellular Ca2+ dynamics by promoting IP3R3-mediated Ca2+ flux to mitochondria.[38] In addition, BAP1 is also reported to play a role in regulating mitochondrial respiration and cellular transformation and thus modulates cells sensitivity to apoptosis.[37] Zhang et al. demonstrated that cystine transporter solute carrier family 7 member 11 (SLC7A11) is repressed by BAP1 and that induces ferroptosis, a nonapoptotic cell death, in tumor.[39] This study added a new horizon to cellular death brought by tumor suppressor function of BAP1 as has been reviewed.[20] Another BAP1-mediated cell death was shown by Sime et al. that association of BAP1 with 14-3-3 protein induces the release of apoptotic inducer protein Bax and that augments apoptotic cell death in neuroblastoma.[40] Differential localization and functional consequences of BAP1 in the nucleus and ER provides a mechanistic insight of BAP1-mediated deubiquitination potential in tumor suppressor activity. There are comparative biological differences across different genus in BAP1 functions as shown canine melanoma and that further signifies a different route of BAP1 regulation.[41]
Table 1: Different BRCA1-associated protein 1 domains with their functions, location of reported germ line mutations, and interaction partners

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  Bap1 Phosphorylation and Cancer Top

BAP1 harbors several phosphosites and are differentially phosphorylated under normal and genotoxic states. Mutations in these residues drastically alter the physiological function of BAP1. The molecular characterization of UBQs and DUBs on large no of patients from around 33 different cancers was performed using The Cancer Genome  Atlas More Details database, and that showed loss of function of BAP1 mutations.[42] The study emphasized the functional importance of the residues undergoing mutations. Proteomic studies have suggested several putative sites of phosphorylation in BAP1, including five serine residues within a fifteen residue stretch (583, 592, 595, 596, and 597) that get altered after genetic insult and DNA damage.[43] In another study, Yu et al. generated both individual (T273A, S276A, and S592A) and combinatorial (S276A/S592A) sets of BAP1 phosphomutants and demonstrated that combinatorial mutant-harboring H226 cells failed to respond genetic insults.[10] Recently shown in a study that gemcitabine induced significantly reduced DNA damage (DSB) and a low degree of apoptosis in malignant mesothelioma cells with BAP1 mutation.[44] These reports advocate the importance of BAP1 residues in its functional status. A study by Eletr et al. in 2013 indicated that phosphorylation at S592, within a consensus ATM/ATR site, leads to dissociation of BAP1 off the chromatin and modifies genes involved in DNA replication and repair.[45] The study was further extended in the following year by Ismail et al. who demonstrated that BAP1 phosphorylation at S592 is ATM-dependent post-DNA-damage and BAP1 recruitment at damage site is dependent on poly (ADP-ribose) activity.[46] S592 phosphorylation is not affected by BAP1 lacking HCF-1 binding motif (HBM), suggesting dispensability of HCF-1 for ATM-mediated phosphorylation of BAP1.[10] As previous studies suggest, as a consequence of BAP1 inactivation, defects in the checkpoint(s) signaling could promote the survival of cells harboring damaged DNA, thus driving neoplastic transformation. However, BAP1-mediated tumor suppression appears to be a complex sequence of events that may activate multiple pathways, thereby regulating the cell cycle in a manner that results in apoptosis, necrosis, or both.[26] Phosphoproteomics analysis has revealed many phosphoresidues on BAP1 protein, and the majority of them have remained biologically uncharacterized as shown in [Table 2].[47],[48],[49],[50],[51],[52],[53] Yu et al. first time showed that BAP1 catalytic activity and its phosphorylation are critical for promoting cellular recovery from DNA damage and in DSB repair by HR, thereby suggesting a molecular-based tumor suppressor function of BAP1.[10] A study by Okino et al. examined the interaction of BAP1 with FoxK2, a Fox transcription factor, and proposed that FoxK2-mediated recruitment of BAP1 is dependent on phosphorylation of T493 residue and that in turn promote DUB activity of BAP1.[54] Apart from T493, phosphorylation of S369 and S585 residues on BAP1 has solely been found under normal physiological condition,[10],[54] while S123, S292, S327, S369, S395, T487, S489, S505, S509, S513, S521, and S597 residues remain phosphorylated under both normal and stressed condition.[10] Under genotoxic stress, T273, T276, S571, S583, and S592 residues are solely phosphorylated while S597 (as highlighted in yellow in the figure) is found to be phosphorylated along with S583 and S592 as depicted in [Figure 3].[10]
Table 2: Phosphoresidues of BRCA1-associated protein 1 assigned under the physiological and stressed condition

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Figure 3: The protein sequence of BRCA1-associated protein 1 showing phosphoresidues: Phosphoresidues, shown here in red color, have been assigned by biological experimentation. Residues S571, S583, S592, and S597 have been shown to be phosphorylated under cellular insult. Residue S597 is always phosphorylated along with either S583 (S583/S597) or S592 (S592/S597)

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Except for S592, no other phosphoresidues (P-residues) had been explored from a physiological perspective to date. Moreover, all these P-residues described above indicate the number of possibilities the PTP can be explored further. This P-residues location on different domains of BAP1 may initially be explored in devising the mechanistic effect of PTP on BAP1 activity in the growth suppression of cancer cells.

  Conclusion Top

There are innumerable instances of PTMs of BAP1, and other DUBs, the protein phosphorylation aspect of BAP1 remained unexplored to a great extent. We mustered the available literature pertaining to BAP1 phosphorylation and proposed that future investigations on PTP-aspect are likely to reveal the regulatory mechanisms to modulate BAP1-DUP activity and function in cellular transformation. Another aspect is multi-PTP crosstalk, where it is likely that some priming phosphorylation events would take place before the functional phosphorylation of residues. As DUBs are highly regulated enzymes, the multi-PTP cross talk has to be carefully examined. The already discovered P-residues modifications are needed to be extensively studied to widen our mechanistic understanding of BAP1 regulation and to lead to the introduction of BAP1-targeting molecular therapies against cancer. Since BAP1 and other DUBs are implicated in cancer and other diseases; therefore, an exhaustive investigation of the PTP-mediated regulation of BAP1 might suggest novel strategies in designing potent inhibitors against BAP1 for the appreciation of its pharmacology. BAP1 plays multiple roles as a master regulator in several vital cellular processes such as genomic stability, proliferation, senescence, and cell death. Loss of function of BAP1 has been implicated in chemoresistance.[55] Therefore, BAP1 gene therapy in different cancer with loss or mutation of BAP1 is thought to be a good strategy against intractable cancer with chemoresistance. This review underscores the urgency of the development of effective strategies for the control of epigenetic drivers of chemoresistance, among the plausible causes. Recently, Phase II clinical studies of BAP1 targeting several cancers are ongoing [Table 3].[56]
Table 3: BRCA1-associated protein 1 related clinical trials

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Based on the discussion, we are putting the following points for the readers and researchers for their appreciation. First, what are the putative phosphorylation sites in BAP1 contributing to its DUB activity? Second, what phosphosites of BAP1 are modulated in the evasion of tumorigenesis? And finally, what are the possible liabilities exhibited by this PTP-deubiquitination machinery, that can be leveraged for cancer therapy?

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Conflicts of interest

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  [Table 1], [Table 2], [Table 3]


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