BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression

Jensen, David E.; Proctor, Monja L.; Marquis, Sandra T.; Gardner, Heather Perry; Ha, Seung I.; Chodosh, Lewis A.; Ishov, Alexander M.; Tommerup, Niels; Vissing, Henrik; Sekido, Yoshitaka; Minna, John D.; Borodovsky, Anna; Schultz, D.; Wilkinson, Keith D.; Maul, Gerd G.; Barlev, Nickolai A.; Berger, Shelley L.; Prendergast, George C.; Rauscher, Frank J.

doi:10.1038/sj.onc.1201861

Cited by 617 publications

(586 citation statements)

References 58 publications

(77 reference statements)

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“…One possibility, however, is that the UM cells bypass the premature stop codon by using alternative splice sites 57 and/or read‐through translation 58 to generate misfolded proteins that are not able to exit the Golgi following processing. Consistent with this, Jensen et al , who first described BAP1, identified a number of putative N‐linked BAP1 glycosylation sites, suggesting that BAP1 may traverse the Golgi during maturation 30. Bhattacharya and colleagues 59 suggested an alternative mechanism for the observation of ‘focal perinuclear’ cBAP1 in the form of cBAP1 aggregates promoted by BAP1 mutations, which expose hydrophobic regions of the protein, leading to beta amyloid aggregation.…”

Section: Discussionmentioning

confidence: 87%

“…The 729‐amino acid BAP1 protein includes an N‐terminal catalytic domain, a bipartite C‐terminal nuclear localisation signal (NLS), and binding domains for BRCA1 (Breast Cancer 1), BARD1 (BRCA1‐associated RING domain protein 1), and HCF1 (Host cell factor 1), among others 30, 31, 32. BAP1 has multiple functions, including involvement in DNA damage responses 33, 34, 35, transcriptional activation 35, chromatin remodelling 36, and cell cycle regulation 33, 37.…”

Section: Introductionmentioning

confidence: 99%

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Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow‐up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1‐positiveM3 UMs were associated with prolonged survival compared to nBAP1‐negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing ‘predominantly diffuse’ in most nBAP1‐negative UM, a distinct ‘focal perinuclear’ expression pattern – localized immediately adjacent to the cis Golgi – was seen in 31% (18/59). These tumours tended to carry loss‐of‐function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non‐genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1‐negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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“…[18][19][20][21][22][23][24][25][26][27] BAP1 is an ubiquitin carboxy-terminal hydrolase which binds to the BRCA1 RING finger domain and enhances BRCA1 growth suppression properties. 28 BAP1 was suggested to regulate the BRCA1/BRCA2-RAD51 DNA repair complex. 29 Given the known implication of BRCA1 in DNA repair 12 and its interaction with RNA pol II, 11 which is linked to transcription-coupled repair (TCR) processes, a role for BAP1 in TCR has been suggested.…”

Section: Introductionmentioning

confidence: 99%

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

et al. 2009

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Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes. Given the high susceptibility conferred by the two major breast cancer predisposition genes, BRCA1 and BRCA2 and the implication of these genes in many key cellular processes, assessment of genes encoding BRCA1-interacting proteins as plausible breast cancer candidate genes is thus attractive. In this study, four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. Although no deleterious truncating germline mutations or aberrant spliced mRNA species were identified, a total of 10, 4, 11 and 6 variants were found in the AURKA, BAP1, BARD1 and DHX9 genes, respectively. The allele frequency of each variant was further ascertained in a cohort of 98 healthy French Canadian unrelated women and a difference in allele frequency was observed for one BARD1 variant based on single-marker analysis. Haplotype estimation, haplotype blocks and tagging SNPs identification were then performed for each gene, providing a valuable tool for further searches of common disease-associated variants in these genes and therefore further analyses on these genes in larger cohorts is warranted in the search of low-to-moderate penetrance breast cancer susceptibility alleles.

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“…Its nuclear functions include inhibition of cell growth [1], induction of apoptosis [2], and regulation of the cell cycle [3]; as well as serving as a transcriptional co-activator [4], an E3 ubiquitin ligase [5] and a caretaker in maintaining genomic integrity [6,7]. The known nonnuclear function of BRCA1 is to regulate centrosome duplication [8].…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1

Hinton

Fitzgerald

Thompson

2007

Experimental Cell Research

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Signaling pathways involved in regulating nuclear-cytoplasmic distribution of BRCA1 have not been previously reported. Here, we provide evidence that heregulin β1-induced activation of the Akt pathway increases the nuclear content of BRCA1. First, treatment of T47D breast cancer cells with heregulin β1 results in a two-fold increase in nuclear BRCA1 as assessed by FACS analysis, immunoblotting and immunofluorescence. This heregulin-induced increase in nuclear BRCA1 is blocked by siRNA-mediated down-regulation of Akt. Second, mutation of threonine 509 in BRCA1, the site of Akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce BRCA1 nuclear accumulation. These data suggest that Akt-catalyzed phosphorylation of BRCA1 is required for the heregulin-regulated nuclear concentration of BRCA1. Because most functions ascribed to BRCA1 occur within the nucleus, we postulated that phosphorylation-dependent nuclear accumulation of BRCA1 would result in enhanced nuclear activity, specifically transcriptional activity, of BRCA1. This postulate is affirmed by our observation that the ability of BRCA1 to transactivate GADD45 promoter constructs was enhanced in T47D cells treated with heregulin β1. Furthermore, the heterologous expression of BRCA1 in HCC1937 human breast cancer cells, which have constitutively active Akt, also induces GADD45 promoter activity, whereas the expression of BRCA1 in which threonine 509 has been mutated to an alanine is able to only minimally induce promoter activity. These findings implicate Akt in upstream events leading to BRCA1 nuclear localization and function.

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BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression

Cited by 617 publications

References 58 publications

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1

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