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Irmgard Irmingerfinger – 1st expert on this subject based on the ideXlab platform

  • BARD1 splice variants display mislocalization in breast cancer cells and can alter the apoptotic response to cisplatin
    Cancer Letters, 2016
    Co-Authors: Kamila A Marzec, Irmgard Irmingerfinger, Estefania Martinoecharri, Beric R Henderson

    Abstract:

    Abstract We previously showed that BARD1 is a shuttling protein with pro-apoptotic activity in MCF-7 breast cancer cells. BARD1 is expressed as splice variant isoforms in breast cancer. Here we characterized YFP-tagged BARD1 splice variants (beta, omega, phi, ΔRIN, epsilon) for subcellular localization and apoptotic efficacy. We found that loss of nuclear localization (NLS) or export (NES) sequences influenced cellular distribution. The beta and omega variants (+NLS/−NES) shifted exclusively to the nucleus. In contrast, BARD1-epsilon (−NLS/+NES) was mostly cytoplasmic. Variants that lacked both NLS and NES were evenly distributed. Interestingly, the more nuclear isoforms (omega and beta) were least apoptotic in MCF-7 cells as measured by FACS. The cytoplasmic localization of BARD1 isoforms correlated with increased apoptosis. This relationship held in cells exposed to low dose (5 µM) of cisplatin. At 20 µM cisplatin, the main observation was a protective effect by the omega isoform. Similar analyses of HCC1937 cells revealed less pronounced changes but a significant protective influence by BARD1-epsilon. Thus BARD1 variants differ in localization and apoptotic ability, and their expression profile may aid prediction of drug efficacy in breast cancer.

  • new concepts on BARD1 regulator of brca pathways and beyond
    The International Journal of Biochemistry & Cell Biology, 2016
    Co-Authors: Irmgard Irmingerfinger, Magda Ratajska, Maxim Pilyugin

    Abstract:

    For nearly two decades most research on BARD1 was closely linked to research on BRCA1, the breast cancer predisposition gene. The co-expression of BARD1 and BRCA1 genes in most tissues, the nearly identical phenotype of BARD1 and Brca1 knock-out mice, and the fact that BRCA1 and BARD1 proteins form a stable complex, led to the general assumption that BARD1 acts as an accessory to BRCA1. More recent research on both proteins showed that BRCA1 and BARD1 might have common as well as separate functions. This review is an overview of how BARD1 functions and controls BRCA1. It highlights also experimental evidence for dominant negative, tumor promoting, functions of aberrant isoforms of BARD1 that are associated with and drivers of various types of cancer.

  • long non coding rna and micrornas might act in regulating the expression of BARD1 mrnas
    The International Journal of Biochemistry & Cell Biology, 2014
    Co-Authors: Maxim Pilyugin, Irmgard Irmingerfinger

    Abstract:

    Abstract Long non-coding RNAs (lncRNAs) are ubiquitously expressed RNA molecules of more than 200 nucleotides without substantial ORFs. LncRNAs could act as epigenetic regulators of gene expression affecting transcription, mRNA stability and transport, and translation, although, precise functions have been attributed to only few of them. Competing endogenous RNAs (ceRNAs) represent one recently emerged type of functional lncRNAs that share microRNA recognition sequences with mRNAs and may compete for microRNA binding and thus affect regulation and function of target mRNAs. We studied the epigenetic regulation of the BARD1 gene. The BARD1 protein acts as tumor suppressor with BRCA1. In cancer, mRNAs encoding the tumor suppressor full length BARD1 are often down-regulated while the expression of oncogenic truncated isoforms is boosted. We found that the BARD1 3′UTR is almost 3000 nt long and harbors a large number of microRNA binding elements. In addition we discovered a novel lncRNA, BARD1 9′L, which is transcribed from an alternative promoter in intron 9 of the BARD1 gene and shares part of the 3′UTR with the protein coding BARD1 mRNAs. We demonstrate with the example of two microRNAs, miR-203 and miR-101, that they down-regulate the expression of FL BARD1 and cancer-associated BARD1 mRNAs, and that BARD1 9′L counteracts the effect of miR-203 and miR-101, As BARD1 9′L is abnormally over-expressed in human cancers, we suggest it might be a tumor promoting factor and treatment target. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.

Richard Baer – 2nd expert on this subject based on the ideXlab platform

  • the brct domains of the brca1 and BARD1 tumor suppressors differentially regulate homology directed repair and stalled fork protection
    Molecular Cell, 2018
    Co-Authors: David Billing, Matthias Szabolcs, Michiko Horiguchi, Foon Wubaer, Angelo Taglialatela, Giuseppe Leuzzi, Silvia Alvarez Nanez, Wenxia Jiang, Alberto Ciccia, Richard Baer

    Abstract:

    Summary The BRCA1 tumor suppressor preserves genome integrity through both homology-directed repair (HDR) and stalled fork protection (SFP). In vivo, BRCA1 exists as a heterodimer with the BARD1 tumor suppressor, and both proteins harbor a phosphate-binding BRCT domain. Here, we compare mice with mutations that ablate BRCT phospho-recognition by BARD1 (BARD1S563F and BARD1K607A) or Brca1 (Brca1S1598F). Brca1S1598F abrogates both HDR and SFP, suggesting that both pathways are likely impaired in most BRCA1 mutant tumors. Although not affecting HDR, the BARD1 mutations ablate poly(ADP-ribose)-dependent recruitment of BRCA1/BARD1 to stalled replication forks, resulting in fork degradation and chromosome instability. Nonetheless, BARD1S563F/S563F and BARD1K607A/K607A mice, unlike Brca1S1598F/S1598F mice, are not tumor prone, indicating that HDR alone is sufficient to suppress tumor formation in the absence of SFP. Nevertheless, because SFP, unlike HDR, is also impaired in heterozygous Brca1/BARD1 mutant cells, SFP and HDR may contribute to distinct stages of tumorigenesis in BRCA1/BARD1 mutation carriers.

  • the basal like mammary carcinomas induced by brca1 or BARD1 inactivation implicate the brca1 BARD1 heterodimer in tumor suppression
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Reena Shakya, Richard Baer, Ellen Mccarthy, Subhadra V Nandula, Vundavalli V Murty, Matthias Szabolcs, Elson Ospina, Katia Basso, Thomas Ludwig

    Abstract:

    Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either BARD1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional BARD1– and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional BARD1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are “triple negative” for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of BARD1-, Brca1-, and BARD1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer.

  • The basal-like mammary carcinomas induced by Brca1 or BARD1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Reena Shakya, Richard Baer, Subhadra V Nandula, Vundavalli V Murty, Matthias Szabolcs, Elson Ospina, Katia Basso, Ellen E. Mccarthy, Thomas Ludwig

    Abstract:

    Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either BARD1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional BARD1– and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional BARD1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are “triple negative” for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of BARD1-, Brca1-, and BARD1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer.

Tomohiko Ohta – 3rd expert on this subject based on the ideXlab platform

  • interaction of BARD1 and hp1 is required for brca1 retention at sites of dna damage
    Cancer Research, 2015
    Co-Authors: Wenwen Wu, Hiroyuki Nishikawa, Rachel E Klevit, Takayo Fukuda, Vinayak Vittal, Masahide Asano, Yasuo Miyoshi, Tomohiko Ohta

    Abstract:

    Stable retention of BRCA1/BARD1 complexes at sites of DNA damage is required for the proper response to DNA double-strand breaks (DSB). Here, we demonstrate that the BRCT domain of BARD1 is crucial for its retention through interaction with HP1. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent but RNF168-independent manner. This interaction is mediated primarily by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacted with the chromoshadow domain of HP1 in vitro. Mutations in this motif (or simultaneous depletion of all three HP1 isoforms) disrupted retention of BARD1, BRCA1 and CtIP at DSB sites and allowed ectopic accumulation of RIF1, an effector of non-homologous end joining, at damaged loci in S phase. UNC0638, a small molecule inhibitor of histone lysine methyltransferase (HKMT), abolished retention and cooperated with the poly(ADP-ribose) polymerase inhibitor olaparib to block cancer cell growth. Taken together, our findings show how BARD1 promotes retention of the BRCA1/BARD1 complex at damaged DNA sites, and suggest the use of HKMT inhibitors to leverage the application of PARP inhibitors to treat breast cancer.

  • BRCA1-Associated Protein 1 Interferes with BRCA1/BARD1 RING Heterodimer Activity
    Cancer Research, 2009
    Co-Authors: Hiroyuki Nishikawa, Wenwen Wu, Mamoru Fukuda, Ayaka Koike, Ryoko Kojima, Hiromichi Gomi, Tomohiko Ohta

    Abstract:

    The breast and ovarian tumor suppressor BRCA1 constitutes a RING heterodimer E3 ligase with BARD1. BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that bound to the RING finger domain of BRCA1. However, how BAP1 contributes to the E3 activity of BRCA1/BARD1 is unclear. Here, we report that BAP1 interacts with BARD1 to inhibit the E3 ligase activity of BRCA1/BARD1. Domains comprised by residues 182-365 of BAP1 interact with the RING finger domain of BARD1, and surface plasmon resonance spectroscopy (BIAcore) analyses showed that BAP1 interferes with the BRCA1/BARD1 association. The perturbation resulted in inhibition of BRCA1 autoubiquitination and NPM1/B23 ubiquitination by BRCA1/BARD1. Although BAP1 was capable of deubiquitinating the polyubiquitin chains mediated by BRCA1/BARD1 in vitro , a catalytically inactive mutant of BAP1, C91S, still inhibited the ubiquitination in vitro and in vivo , implicating a second mechanism of action. Importantly, inhibition of BAP1 expression by short hairpin RNA resulted in hypersensitivity of the cells to ionizing irradiation and in retardation of S-phase progression. Together, these results suggest that BAP1 and BRCA1/BARD1 coordinately regulate ubiquitination during the DNA damage response and the cell cycle. [Cancer Res 2009;69(1):111–9]

  • brca1 associated protein 1 interferes with brca1 BARD1 ring heterodimer activity
    Cancer Research, 2009
    Co-Authors: Hiroyuki Nishikawa, Wenwen Wu, Mamoru Fukuda, Ayaka Koike, Ryoko Kojima, Hiromichi Gomi, Tomohiko Ohta

    Abstract:

    The breast and ovarian tumor suppressor BRCA1 constitutes a RING heterodimer E3 ligase with BARD1. BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that bound to the RING finger domain of BRCA1. However, how BAP1 contributes to the E3 activity of BRCA1/BARD1 is unclear. Here, we report that BAP1 interacts with BARD1 to inhibit the E3 ligase activity of BRCA1/BARD1. Domains comprised by residues 182-365 of BAP1 interact with the RING finger domain of BARD1, and surface plasmon resonance spectroscopy (BIAcore) analyses showed that BAP1 interferes with the BRCA1/BARD1 association. The perturbation resulted in inhibition of BRCA1 autoubiquitination and NPM1/B23 ubiquitination by BRCA1/BARD1. Although BAP1 was capable of deubiquitinating the polyubiquitin chains mediated by BRCA1/BARD1 in vitro , a catalytically inactive mutant of BAP1, C91S, still inhibited the ubiquitination in vitro and in vivo , implicating a second mechanism of action. Importantly, inhibition of BAP1 expression by short hairpin RNA resulted in hypersensitivity of the cells to ionizing irradiation and in retardation of S-phase progression. Together, these results suggest that BAP1 and BRCA1/BARD1 coordinately regulate ubiquitination during the DNA damage response and the cell cycle. [Cancer Res 2009;69(1):111–9]