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Open AccessArticle

Mutational Landscape of the BAP1 Locus Reveals an Intrinsic Control to Regulate the miRNA Network and the Binding of Protein Complexes in Uveal Melanoma

1
Department of Ophthalmology, University Hospital Bonn, 53127 Bonn, Germany
2
Institute of Experimental Hematology and Transfusion Medicine, University Clinic of Bonn, 53127 Bonn, Germany
3
State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China
4
Department of Computer Science and Engineering, Jadavpur University, Kolkata 700032, India
5
Department of Internal Medicine, Division of Medical Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
6
Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, TX 77030, USA
7
Department of Biotechnology, Mohanlal Sukhadia University, Rajasthan 313001, India
8
Department of Biotechnology, Bhupat and Jyoti Mehta School of BioSciences, Indian Institute of Technology Madras, Chennai, Tamilnadu 600036, India
9
Indian Statistical Institute, Kolkata, West Bengal 700108, India
10
Department of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, 53127 Bonn, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this manuscript.
Cancers 2019, 11(10), 1600; https://doi.org/10.3390/cancers11101600
Received: 13 September 2019 / Revised: 13 October 2019 / Accepted: 16 October 2019 / Published: 19 October 2019
(This article belongs to the Collection Application of Bioinformatics in Cancers)
The BAP1 (BRCA1-associated protein 1) gene is associated with a variety of human cancers. With its gene product being a nuclear ubiquitin carboxy-terminal hydrolase with deubiquitinase activity, BAP1 acts as a tumor suppressor gene with potential pleiotropic effects in multiple tumor types. Herein, we focused specifically on uveal melanoma (UM) in which BAP1 mutations are associated with a metastasizing phenotype and decreased survival rates. We identified the ubiquitin carboxyl hydrolase (UCH) domain as a major hotspot region for the pathogenic mutations with a high evolutionary action (EA) score. This also includes the mutations at conserved catalytic sites and the ones overlapping with the phosphorylation residues. Computational protein interaction studies revealed that distant BAP1-associated protein complexes (FOXK2, ASXL1, BARD1, BRCA1) could be directly impacted by this mutation paradigm. We also described the conformational transition related to BAP1-BRCA-BARD1 complex, which may pose critical implications for mutations, especially at the docking interfaces of these three proteins. The mutations affect - independent of being somatic or germline - the binding affinity of miRNAs embedded within the BAP1 locus, thereby altering the unique regulatory network. Apart from UM, BAP1 gene expression and survival associations were found to be predictive for the prognosis in several (n = 29) other cancer types. Herein, we suggest that although BAP1 is conceptually a driver gene in UM, it might contribute through its interaction partners and its regulatory miRNA network to various aspects of cancer. Taken together, these findings will pave the way to evaluate BAP1 in a variety of other human cancers with a shared mutational spectrum. View Full-Text
Keywords: BAP1; uveal melanoma; UCH domain; miRNAs; TCGA; HCF-1; FOXK2; ASXL1; BARD1; BRCA1; evolutionary action score BAP1; uveal melanoma; UCH domain; miRNAs; TCGA; HCF-1; FOXK2; ASXL1; BARD1; BRCA1; evolutionary action score
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Sharma, A.; Biswas, A.; Liu, H.; Sen, S.; Paruchuri, A.; Katsonis, P.; Lichtarge, O.; Chand Dakal, T.; Maulik, U.; Gromiha, M.M.; Bandyopadhyay, S.; Ludwig, M.; Holz, F.G.; Loeffler, K.U.; Herwig-Carl, M.C. Mutational Landscape of the BAP1 Locus Reveals an Intrinsic Control to Regulate the miRNA Network and the Binding of Protein Complexes in Uveal Melanoma. Cancers 2019, 11, 1600.

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