|Year : 2019 | Volume
| Issue : 2 | Page : 25-32
Phosphorylation of BRCA1-associated protein 1 as an important mechanism in the evasion of tumorigenesis: A perspective
Guru Prasad Sharma1, Anjali Geethadevi2, Jyotsna Mishra3, G Anupa4, Kapilesh Jadhav5, KS Vikramdeo6, Deepak Parashar2
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 Submission||10-Feb-2019|
|Date of Acceptance||20-Apr-2019|
|Date of Web Publication||28-Jun-2019|
Dr. Deepak Parashar
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee 53226, Wisconsin
Source of Support: None, Conflict of Interest: None
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 2019 Sep 20];5:25-32. Available from: http://www.cancertm.com/text.asp?2019/5/2/25/261825
| Introduction|| |
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. 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. 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., 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, and remaining DUBs are metalloproteases. DUB activity of BAP1 is attributed to its complex structure composition known as polycomb repressive-DUB (PR-DUB). 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. Mechanistic insights of Calypso/ASX complex have further provided opportunity in intervening the mechanism-based therapeutics against BAP1/ASXL-related human tumors. Human PR-DUB is composed of BAP1 and one of three regulatory ASX-Like proteins (ASXL1/2/3). BAP1, also a tumor suppressor protein, is mutated/inactivated in various types of cancer. 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. 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.,
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,, and proteolytic cleavage. Posttranslational modification (PTM) itself includes different regulatory processes versus monoubiquitination, sumoylation, acetylation, and phosphorylation. Recent reports have revealed that phosphorylated BAP1 is recruited to double-strand DNA break sites and promotes DNA repair by coordinating H2A ubiquitination. BAP1 has been found to play critical roles in the epigenetic modification, transcription regulation, DNA damage response (DDR), and cell death. 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|| |
BAP1 is a nuclear DUB which interacts with multiprotein complexes as shown in [Figure 1]. 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. 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. By binding and deubiquitinating BARD1, BAP1 modulates the E3 ubiquitin ligase activity of BRCA1-BARD1 complex, and this regulates DDR. As shown diagrammatically [Figure 2], the tumor suppressor activity of BAP1 is performed by modulating cell cycle, cellular differentiation, cell death, DDR, transcriptional regulation, chromatin modulation, and gluconeogenesis.
|Figure 1: Interaction of BRCA1-associated protein 1 with multiprotein complexes|
Click here to view
|Figure 2: Major role of BRCA1-associated protein 1 as a tumor suppressor protein|
Click here to view
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. 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. For instance, BAP1 deubiquitinates HCF-1, and this association is a prerequisite for growth inhibition in RCC cell line. Moreover, an association of BAP1/ASXL1 complex has been shown to help deubiquitin histone H2A in human and mouse cancer cell lines. 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. 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. Exceptionally, studies suggest that BAP1 does not appear to function in the deubiquitination of the BRCA1/BARD1 complex. 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., Such familial cancer is termed as BAP1 cancer predisposition syndrome and has recently been reviewed in UM. Somatic mutations have been reported to be associated with metastases in many cancer,, 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. 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. 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]. BAP1 deletion leads to the development of immature T and B lymphocytes resulting in a wide range of tumors. 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. 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. Recent studies have demonstrated extra-nuclear localization of BAP1, in the cytoplasm specifically in the endoplasmic reticulum (ER). 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. In addition, BAP1 is also reported to play a role in regulating mitochondrial respiration and cellular transformation and thus modulates cells sensitivity to apoptosis. 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. This study added a new horizon to cellular death brought by tumor suppressor function of BAP1 as has been reviewed. 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. 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.
|Table 1: Different BRCA1-associated protein 1 domains with their functions, location of reported germ line mutations, and interaction partners|
Click here to view
| Bap1 Phosphorylation and Cancer|| |
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. 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. 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. 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. 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. 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. S592 phosphorylation is not affected by BAP1 lacking HCF-1 binding motif (HBM), suggesting dispensability of HCF-1 for ATM-mediated phosphorylation of BAP1. 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. Phosphoproteomics analysis has revealed many phosphoresidues on BAP1 protein, and the majority of them have remained biologically uncharacterized as shown in [Table 2].,,,,,, 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. 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. Apart from T493, phosphorylation of S369 and S585 residues on BAP1 has solely been found under normal physiological condition,, while S123, S292, S327, S369, S395, T487, S489, S505, S509, S513, S521, and S597 residues remain phosphorylated under both normal and stressed condition. 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].
|Table 2: Phosphoresidues of BRCA1-associated protein 1 assigned under the physiological and stressed condition|
Click here to view
|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)|
Click here to view
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|| |
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. 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].
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?
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene
1998; 16(9): 1097.
Eletr ZM, Wilkinson KD. Regulation of proteolysis by human deubiquitinating enzymes. Biochim Biophys Acta Mol Cell Res
2014; 1843(1): 114–28.
Wilkinson KD. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J
1997; 11(14): 1245–56.
Fraile JM, Quesada V, Rodríguez D, Freije JM, López-Otín C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene
2012; 31(19): 2373–88.
Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell
2005; 123(5): 773–86.
Chittock EC, Latwiel S, Miller TC, Müller CW. Molecular architecture of polycomb repressive complexes. Biochem Soc Trans
2017; 45(1): 193–205.
Scheuermann JC, De Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J. Histone H2A deubiquitinase activity of the polycomb repressive complex PR-DUB. Nature
2010; 465(7295): 243.
De I, McCarthy AA, Chittock EC, Grötsch H, Miller TC, Müller CW. Structural basis for the activation of the deubiquitinase calypso by the polycomb protein ASX. Structure
2019; 27(3): 528–36.
Sahtoe DD, Van Dijk WJ, Ekkebus R, Ovaa H, Sixma TK. BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat Commun
2016; 7: 10292.
Yu H, Pak H, Hammond-Martel I, Ghram M, Rodrigue A, Daou S, Barbour H, Corbeil L, Hebert J, Drobetsky E, Masson JY, Di Noia JM, Affar EB. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci
2014; 111(1): 285–90.
Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer
2013; 13(3): 153–9.
Bednash JS, Mallampalli RK. Targeting deubiquitinases in cancer. In: Proteases and cancer. New York: Humana Press; 2018. p. 295-305.
Wei R, Liu X, Yu W, Yang T, Cai W, Liu J, Huang X, Xu G, Zhao S, Yang J, Liu S. Deubiquitinases in cancer. Oncotarget
2015; 6(15): 12872–89.
Ventii KH, Wilkinson KD. Protein partners of deubiquitinating enzymes. Biochem J
2008; 414(2): 161–75.
Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell
2009; 138(2): 389–403.
Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol
2006; 8(4): 341.
Kessler BM, Edelmann MJ. PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications. Cell Biochem Biophys
2011; 60(1-2): 21–38.
Ji Z, Mohammed H, Webber A, Ridsdale J, Han N, Carroll JS, Sharrocks AD. The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex. Nucleic Acids Res
2014; 42(10): 6232–42.
Peng J, Ma J, Li W, Mo R, Zhang P, Gao K, Jin X, Xiao J, Wang C, Fan J. Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma. Cancer Lett
2015; 369(1): 167–74.
Affar EB, Carbone M. BAP1 regulates different mechanisms of cell death. Cell Death Dis
2018; 9(12): 1151.
Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright G, Bader GD, Morris Q. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res
2010; 38(Suppl 2): W214–20.
Wang XY, Wang Z, Huang JB, Ren XD, Ye D, Zhu WW, Qin LX. Tissue-specific significance of BAP1 gene mutation in prognostic prediction and molecular taxonomy among different types of cancer. Tumor Biol
2017; 39(6): 1010428317699111.
Kolluri KK, Alifrangis C, Kumar N, Ishii Y, Price S, Michaut M, Williams S, Barthorpe S, Lightfoot H, Busacca S, Sharkey A, Yuan Z, Sage EK, Vallath S, Le Quesne J, Tice DA, Alrifai D, von Karstedt S, Montinaro A, Guppy N, Waller DA, Nakas A, Good R, Holmes A, Walczak H, Fennell DA, Garnett M, Iorio F, Wessels L, McDermott U, Janes SM. Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells. Elife
2018; 7: e30224.
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Wong SW, Grishin N, Laurent M, Xie X, Christian D, Ross MT, Bentley DR, Kapur P, Brugarolas J. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet
2013; 44(7): 751–9.
Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, Zhao L, Bennett AM, Samuel VT, Wu J, Yates JR, Yang X. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metab
2012; 16(2): 226–37.
Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res
2008; 68(17): 6953–62.
Zargar Z, Tyagi S. Role of host cell factor-1 in cell cycle regulation. Transcription
2012; 3(4): 187–92.
Daou S, Barbour H, Ahmed O, Masclef L, Baril C, Sen Nkwe N, Tchelougou D, Uriarte M, Bonneil E, Ceccarelli D, Mashtalir N, Tanji M, Masson JY, Thibault P, Sicheri F, Yang H, Carbone M, Therrien M, Affar EB. Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1. Nat Commun
2018; 9(1): 4385.
Mallery DL, Vandenberg CJ, Hiom K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J
2002; 21(24): 6755–62.
Luchini C, Veronese N, Yachida S, Cheng L, Nottegar A, Stubbs B, Solmi M, Capelli P, Pea A, Barbareschi M, Fassan M, Wood LD, Scarpa A. Different prognostic roles of tumor suppressor gene BAP1 in cancer: a systematic review with meta-analysis. Genes Chromosom Cancer
2016; 55(10): 741–9.
Masoomian B, Shields JA, Shields CL. Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol
2018; 30(2): 102–9.
Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science
2010; 330(6009): 1410–3.
Kalirai H, Dodson A, Faqir S, Damato BE, Coupland SE. Lack of BAP1 protein expression in uveal melanoma is associated with increased metastatic risk and has utility in routine prognostic testing. Br J Cancer
2014; 111(7): 1373.
Ewens KG, Lalonde E, Richards-Yutz J, Shields CL, Ganguly A. Comparison of germline versus somatic BAP1 mutations for risk of metastasis in uveal melanoma. BMC Cancer
2018; 18(1): 1172.
Peng H, Prokop J, Karar J, Park K, Cao L, Harbour JW, Bowcock AM, Malkowicz SB, Cheung M, Testa JR, Rauscher FJ. Familial and somatic BAP1 mutations inactivate ASXL1/2-mediated allosteric regulation of BAP1 deubiquitinase by targeting multiple independent domains. Cancer Res
2018; 78(5): 1200–13.
Arenzana TL, Lianoglou S, Seki A, Eidenschenk C, Cheung T, Seshasayee D, Hagenbeek T, Sambandam A, Noubade R, Peng I, Lesch J, DeVoss J, Wu X, Lee WP, Caplazi P, Webster J, Liu J, Pham VC, Arnott D, Lill JR, Modrusan Z, Dey A, Rutz S. Tumor suppressor BAP1 is essential for thymic development and proliferative responses of T lymphocytes. Sci Immunol
2018; 3(22): eaal1953.
Hebert L, Bellanger D, Guillas C, Campagne A, Dingli F, Loew D, Fievet A, Jacquemin V, Popova T, Jean D, Mechta-Grigoriou F, Margueron R, Stern MH. Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function. Oncotarget
2017; 8(42): 72513.
Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, Pellegrini L, Signorato V, Olivetto F, Pastorino S, Nasu M, Napolitano A, Gaudino G, Morris P, Sakamoto G, Ferris LK, Danese A, Raimondi A, Tacchetti C, Kuchay S, Pass HI, Affar EB, Yang H, Pinton P, Carbone M. BAP1 regulates IP3R3-mediated Ca2+flux to mitochondria suppressing cell transformation. Nature
2017; 546(7659): 549.
Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, Sirohi K, Li X, Wei Y, Lee H, Zhuang L, Chen G, Xiao ZD, Hung MC, Chen J, Huang P, Li W, Gan B. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol
2018; 20(10): 1181.
Sime W, Niu Q, Abassi Y, Masoumi KC, Zarrizi R, Køhler JB, Kjellström S, Lasorsa VA, Capasso M, Fu H, Massoumi R. BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma article. Cell Death Dis
2018; 9(5): 458.
Jama N, Farquhar N, Butt Z, Coupland SE, Sacco JJ, Scase T, Fielding AB, Coulson JM, Kalirai H, Killick DR. Altered nuclear expression of the deubiquitylase BAP1 cannot be used as a prognostic marker for canine melanoma. J Comp Pathol
2018; 162: 50–8.
Ge Z, Leighton JS, Wang Y, Peng X, Chen Z, Chen H, Sun Y, Yao F, Li J, Zhang H, Liu J, Shriver CD, Hu H, Caesar-Johnson SJ, Demchok JA, Felau I, Kasapi M, Ferguson ML, Hutter CM, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Cho J, DeFreitas T, Frazer S, Gehlenborg N, Getz G, Heiman DI, Kim J, Lawrence MS, Lin P, Meier S, Noble MS, Saksena G, Voet D, Zhang H, Bernard B, Chambwe N, Dhankani V, Knijnenburg T, Kramer R, Leinonen K, Liu Y, Miller M, Reynolds S, Shmulevich I, Thorsson V, Zhang W, Akbani R, Broom BM, Hegde AM, Ju Z, Kanchi RS, Korkut A, Li J, Liang H, Ling S, Liu W, Lu Y, Mills GB, Ng KS, Rao A, Ryan M, Wang J, Weinstein JN, Zhang J, Abeshouse A, Armenia J, Chakravarty D, Chatila WK, de Bruijn I, Gao J, Gross BE, Heins ZJ, Kundra R, La K, Ladanyi M, Luna A, Nissan MG, Ochoa A, Phillips SM, Reznik E, Sanchez-Vega F, Sander C, Schultz N, Sheridan R, Sumer SO, Sun Y, Taylor BS, Wang J, Zhang H, Anur P, Peto M, Spellman P, Benz C, Stuart JM, Wong CK, Yau C, Hayes DN, Parker JS, Wilkerson MD, Ally A, Balasundaram M, Bowlby R, Brooks D, Carlsen R, Chuah E, Dhalla N, Holt R, Jones SJ, Kasaian K, Lee D, Ma Y, Marra MA, Mayo M, Moore RA, Mungall AJ, Mungall K, Robertson AG, Sadeghi S, Schein JE, Sipahimalani P, Tam A, Thiessen N, Tse K, Wong T, Berger AC, Beroukhim R, Cherniack AD, Cibulskis C, Gabriel SB, Gao GF, Ha G, Meyerson M, Schumacher SE, Shih J, Kucherlapati MH, Kucherlapati RS, Baylin S, Cope L, Danilova L, Bootwalla MS, Lai PH, Maglinte DT, Van Den Berg DJ, Weisenberger DJ, Auman JT, Balu S, Bodenheimer T, Fan C, Hoadley KA, Hoyle AP, Jefferys SR, Jones CD, Meng S, Mieczkowski PA, Mose LE, Perou AH, Perou CM, Roach J, Shi Y, Simons J V., Skelly T, Soloway MG, Tan D, Veluvolu U, Fan H, Hinoue T, Laird PW, Shen H, Zhou W, Bellair M, Chang K, Covington K, Creighton CJ, Dinh H, Doddapaneni HV, Donehower LA, Drummond J, Gibbs RA, Glenn R, Hale W, Han Y, Hu J, Korchina V, Lee S, Lewis L, Li W, Liu X, Morgan M, Morton D, Muzny D, Santibanez J, Sheth M, Shinbrot E, Wang L, Wang M, Wheeler DA, Xi L, Zhao F, Hess J, Appelbaum EL, Bailey M, Cordes MG, Ding L, Fronick CC, Fulton LA, Fulton RS, Kandoth C, Mardis ER, McLellan MD, Miller CA, Schmidt HK, Wilson RK, Crain D, Curley E, Gardner J, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton C, Shelton T, Sherman M, Thompson E, Yena P, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Wise L, Zmuda E, Corcoran N, Costello T, Hovens C, Carvalho AL, de Carvalho AC, Fregnani JH, Longatto-Filho A, Reis RM, Scapulatempo-Neto C, Silveira HC, Vidal DO, Burnette A, Eschbacher J, Hermes B, Noss A, Singh R, Anderson ML, Castro PD, Ittmann M, Huntsman D, Kohl B, Le X, Thorp R, Andry C, Duffy ER, Lyadov V, Paklina O, Setdikova G, Shabunin A, Tavobilov M, McPherson C, Warnick R, Berkowitz R, Cramer D, Feltmate C, Horowitz N, Kibel A, Muto M, Raut CP, Malykh A, Barnholtz-Sloan JS, Barrett W, Devine K, Fulop J, Ostrom QT, Shimmel K, Wolinsky Y, Sloan AE, De Rose A, Giuliante F, Goodman M, Karlan BY, Hagedorn CH, Eckman J, Harr J, Myers J, Tucker K, Zach LA, Deyarmin B, Hu H, Kvecher L, Larson C, Mural RJ, Somiari S, Vicha A, Zelinka T, Bennett J, Iacocca M, Rabeno B, Swanson P, Latour M, Lacombe L, Têtu B, Bergeron A, McGraw M, Staugaitis SM, Chabot J, Hibshoosh H, Sepulveda A, Su T, Wang T, Potapova O, Voronina O, Desjardins L, Mariani O, Roman-Roman S, Sastre X, Stern MH, Cheng F, Signoretti S, Berchuck A, Bigner D, Lipp E, Marks J, McCall S, McLendon R, Secord A, Sharp A, Behera M, Brat DJ, Chen A, Delman K, Force S, Khuri F, Magliocca K, Maithel S, Olson JJ, Owonikoko T, Pickens A, Ramalingam S, Shin DM, Sica G, Van Meir EG, Zhang H, Eijckenboom W, Gillis A, Korpershoek E, Looijenga L, Oosterhuis W, Stoop H, van Kessel KE, Zwarthoff EC, Calatozzolo C, Cuppini L, Cuzzubbo S, DiMeco F, Finocchiaro G, Mattei L, Perin A, Pollo B, Chen C, Houck J, Lohavanichbutr P, Hartmann A, Stoehr C, Stoehr R, Taubert H, Wach S, Wullich B, Kycler W, Murawa D, Wiznerowicz M, Chung K, Edenfield WJ, Martin J, Baudin E, Bubley G, Bueno R, De Rienzo A, Richards WG, Kalkanis S, Mikkelsen T, Noushmehr H, Scarpace L, Girard N, Aymerich M, Campo E, Giné E, Guillermo AL, Van Bang N, Hanh PT, Phu BD, Tang Y, Colman H, Evason K, Dottino PR, Martignetti JA, Gabra H, Juhl H, Akeredolu T, Stepa S, Hoon D, Ahn K, Kang KJ, Beuschlein F, Breggia A, Birrer M, Bell D, Borad M, Bryce AH, Castle E, Chandan V, Cheville J, Copland JA, Farnell M, Flotte T, Giama N, Ho T, Kendrick M, Kocher JP, Kopp K, Moser C, Nagorney D, O'Brien D, O'Neill BP, Patel T, Petersen G, Que F, Rivera M, Roberts L, Smallridge R, Smyrk T, Stanton M, Thompson RH, Torbenson M, Yang JD, Zhang L, Brimo F, Ajani JA, Gonzalez AM, Behrens C, Bondaruk J, Broaddus R, Czerniak B, Esmaeli B, Fujimoto J, Gershenwald J, Guo C, Lazar AJ, Logothetis C, Meric-Bernstam F, Moran C, Ramondetta L, Rice D, Sood A, Tamboli P, Thompson T, Troncoso P, Tsao A, Wistuba I, Carter C, Haydu L, Hersey P, Jakrot V, Kakavand H, Kefford R, Lee K, Long G, Mann G, Quinn M, Saw R, Scolyer R, Shannon K, Spillane A, Stretch J, Synott M, Thompson J, Wilmott J, Al-Ahmadie H, Chan TA, Ghossein R, Gopalan A, Levine DA, Reuter V, Singer S, Singh B, Tien NV, Broudy T, Mirsaidi C, Nair P, Drwiega P, Miller J, Smith J, Zaren H, Park JW, Hung NP, Kebebew E, Linehan WM, Metwalli AR, Pacak K, Pinto PA, Schiffman M, Schmidt LS, Vocke CD, Wentzensen N, Worrell R, Yang H, Moncrieff M, Goparaju C, Melamed J, Pass H, Botnariuc N, Caraman I, Cernat M, Chemencedji I, Clipca A, Doruc S, Gorincioi G, Mura S, Pirtac M, Stancul I, Tcaciuc D, Albert M, Alexopoulou I, Arnaout A, Bartlett J, Engel J, Gilbert S, Parfitt J, Sekhon H, Thomas G, Rassl DM, Rintoul RC, Bifulco C, Tamakawa R, Urba W, Hayward N, Timmers H, Antenucci A, Facciolo F, Grazi G, Marino M, Merola R, de Krijger R, Gimenez-Roqueplo AP, Piché A, Chevalier S, McKercher G, Birsoy K, Barnett G, Brewer C, Farver C, Naska T, Pennell NA, Raymond D, Schilero C, Smolenski K, Williams F, Morrison C, Borgia JA, Liptay MJ, Pool M, Seder CW, Junker K, Omberg L, Dinkin M, Manikhas G, Alvaro D, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Chesla D, Cottingham S, Dubina M, Moiseenko F, Dhanasekaran R, Becker KF, Janssen KP, Slotta-Huspenina J, Abdel-Rahman MH, Aziz D, Bell S, Cebulla CM, Davis A, Duell R, Elder JB, Hilty J, Kumar B, Lang J, Lehman NL, Mandt R, Nguyen P, Pilarski R, Rai K, Schoenfield L, Senecal K, Wakely P, Hansen P, Lechan R, Powers J, Tischler A, Grizzle WE, Sexton KC, Kastl A, Henderson J, Porten S, Waldmann J, Fassnacht M, Asa SL, Schadendorf D, Couce M, Graefen M, Huland H, Sauter G, Schlomm T, Simon R, Tennstedt P, Olabode O, Nelson M, Bathe O, Carroll PR, Chan JM, Disaia P, Glenn P, Kelley RK, Landen CN, Phillips J, Prados M, Simko J, Smith-McCune K, VandenBerg S, Roggin K, Fehrenbach A, Kendler A, Sifri S, Steele R, Jimeno A, Carey F, Forgie I, Mannelli M, Carney M, Hernandez B, Campos B, Herold-Mende C, Jungk C, Unterberg A, von Deimling A, Bossler A, Galbraith J, Jacobus L, Knudson M, Knutson T, Ma D, Milhem M, Sigmund R, Godwin AK, Madan R, Rosenthal HG, Adebamowo C, Adebamowo SN, Boussioutas A, Beer D, Giordano T, Mes-Masson AM, Saad F, Bocklage T, Landrum L, Mannel R, Moore K, Moxley K, Postier R, Walker J, Zuna R, Feldman M, Valdivieso F, Dhir R, Luketich J, Pinero EM, Quintero-Aguilo M, Carlotti CG, Dos Santos JS, Kemp R, Sankarankuty A, Tirapelli D, Catto J, Agnew K, Swisher E, Creaney J, Robinson B, Shelley CS, Godwin EM, Kendall S, Shipman C, Bradford C, Carey T, Haddad A, Moyer J, Peterson L, Prince M, Rozek L, Wolf G, Bowman R, Fong KM, Yang I, Korst R, Rathmell WK, Fantacone-Campbell JL, Hooke JA, Kovatich AJ, Shriver CD, DiPersio J, Drake B, Govindan R, Heath S, Ley T, Van Tine B, Westervelt P, Rubin MA, Lee JI, Aredes ND, Mariamidze A, Piwnica-Worms H, Ma L, Liang H. Integrated genomic analysis of the ubiquitin pathway across cancer types. Cell Rep
2018; 23(1): 213–26.
Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res
2015; 43(D1): D512–20.
Guazzelli A, Bakker E, Meysami P, Giordano A, Krstic-Demonacos M, Demonacos C, Mutti L. BAP1 status determines the sensitivity of malignant mesothelioma cells to gemcitabine treatment. Int J Mol Sci
2019; 20(2): 429.
Eletr ZM, Yin L, Wilkinson KD. BAP1 is phosphorylated at serine 592 in S-phase following DNA damage. FEBS Lett
2013; 587(24): 3906–11.
Ismail IH, Davidson R, Gagné JP, Xu ZZ, Poirier GG, Hendzel MJ. Germline mutations in BAP1 impair its function in DNA double-strand break repair. Cancer Res
2014; 74(16): 4282–94.
Chen RQ, Yang QK, Lu BW, Yi W, Cantin G, Chen YL, Fearns C, Yates JR, Lee JD. CDC25B mediates rapamycin-induced oncogenic responses in cancer cells. Cancer Res
2009; 69(6): 2663–8.
Schweppe DK, Rigas JR, Gerber SA. Quantitative phosphoproteomic profiling of human non-small cell lung cancer tumors. J Proteomics
2013; 91: 286–96.
Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics
2014; 96: 253–62.
Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci
2008; 105(31): 10762–7.
Pighi C, Gu TL, Dalai I, Barbi S, Parolini C, Bertolaso A, Pedron S, Parisi A, Ren J, Cecconi D, Chilosi M, Menestrina F, Zamò A. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol
2011; 34(2): 141–53.
Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S. Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res
2013; 12(1): 260–71.
Sharma K, D'Souza RC, Tyanova S, Schaab C, Wiśniewski JR, Cox J, Mann M. Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep
2014; 8(5): 1583–94.
Okino Y, Machida Y, Frankland-Searby S, Machida YJ. BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes. J Biol Chem
2015; 290(3): 1580–91.
Okonska A, Buehler S, Rao V, Ronner M, Blijlevens M, Van der Meulen-Muileman I, de Menezes R, Smit E, Weder W, Stahel R, Penengo L, van Beusechem V, Felley-Bosco E. Genome-wide silencing screen in mesothelioma cells reveals that loss of function of BAP1 induces chemoresistance to ribonucleotide reductase inhibition: implication for therapy. BioRxiv
National Institute of Health. Home – ClinicalTrials.gov. US National Library of Medicine; 2017.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]