BARD1 Science

bard1-scienceThe BARD1 gene (BRCA1-associated RING domain 1) is a tumour suppressor coding for the protein BARD1, an important protein binding and stabilising the BRCA1 protein[1]. BARD1 and BRCA1 form a stable heterodimer via their RING finger domains, while the respective monomers are unstable[2]. BRCA1 (breast cancer type 1 susceptibility protein) is normally responsible for repairing DNA, whereas BRCA1 mutations have been shown to increase the risk for breast cancer. The BARD1-BRCA1 structural association, and the fact that cancer-associated mutations of BRCA1 and 2 have been found in up to 40-50% of inherited cancers, compared to only a few cancer-associated mutations being found for BARD1[2], led to the currently accepted hypothesis that BARD1 acts as an accessory protein for BRCA1 functions.

However, BARD1, independently of BRCA1, plays a role in mitosis, as recent results showed that BARD1 is specifically required for completion of cytokinesis[3]. BARD1 depletion by siRNA leads to a phenotype reminiscent of upregulation of the mitotic kinase Aurora B[4], depletion of TACC1[5], or depletion of BRCA2[6]. BARD1, like BRCA2, localizes to the midbody at cytokinesis and depletion of BARD1, like BRCA2, leads to cell cycle arrest at cytokinesis. Specifically, the BARD1β isoform, but not “normal” BARD1, forms complexes with Aurora B and BRCA2, suggesting that these proteins act in a common pathway.

However, cancer cells express a number of aberrant BARD1 molecules generated by alternative splicing that antagonize the functions of “normal” BARD1 and BRCA1 functions and act as drivers of oncogenesis[3],[7]. A combination of aberrant BARD1 molecules is specific for different cancers[8],[12]. BARD1 mutations promoting alternative splicing have now been identified in non-coding and coding regions that predispose to cancer[13],[14]. Therefore, it is now suggested that BARD1 epitopes are novel and specific biomarkers for multiple cancers.

3-dimentional structure of BARD1

[1]Wu, L.C., Z.W. Wang, J.T. Tsan, M.A. Spillman, A. Phung, X.L. Xu, M.C. Yang, L.Y. Hwang, A.M. Bowcock, and R. Baer. 1996. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14: 430-40.
[2] Irminger-Finger I, Ratajska M, Pilyugin M. New concepts on BARD1: Regulator of BRCA pathways and beyond. Int J Biochem Cell Biol. 2016 Mar;72:1-17.
[3] Ryser, S., E , C. Dizin, B. Jefford, A. Delaval, N. Christodoulidou, S. Gagos, K.H. Krause, D. Birnbaum, and I. Irminger-Finger. 2009. Distinct roles of BARD1 isoforms in mitosis: full length BARD1 mediates Aurora B degradation, cancer-associated BARD1? scaffolds Aurora B and BRCA2. Cancer Res 69: 1125-34.
[4] Zhang, Y., Y. Nagata, G. Yu, H.G. Nguyen, M.R. Jones, P. Toselli, C.W. Jackson, M. Tatsuka, K. Todokoro, and K. Ravid. 2004. Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of Aurora-B/AIM-1-deregulated expression. Blood 103: 3717-26.
[5] Delaval, B., A. Ferrand, N. Conte, C. Larroque, D. Hernandez-Verdun, C. Prigent, and D. Birnbaum. 2004. Aurora B -TACC1 protein complex in cytokinesis. Oncogene 23: 4516-22.
[6] Daniels, M.J., Y. Wang, M. Lee, and A.R. Venkitaraman. 2004. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306: 876-9.
[7] Bosse KR, Diskin SJ, Cole KA, Wood AC, Schnepp RW, Norris G, Nguyen LB, Jagannathan J, Laquaglia M, Winter C, Diamond M, Hou C, Attiyeh EF, Mosse YP, Pineros V, Dizin E, Zhang Y, Asgharzadeh S, Seeger RC, Capasso M, Pawel BR, Devoto M, Hakonarson H, Rapport EF, Irminger-Finger I, Maris JM. Common Variation at BARD1 Results in the Expression of an Oncogenic Isoform that Influences Neuroblastoma Susceptibility and Oncogenicity. Cancer Res. 2012 Apr 15;72(8):2068-78.
[8] Wu, J.Y., A.T. Vlastos, M.F. Pelte, M.A. Caligo, A. Bianco, K.H. Krause, G.J. Laurent, and I. Irminger-Finger. 2006. Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. Int J Cancer 118: 1215-26.
[9] Li, L., S. Ryser, E. Dizin, D. Pils, M. Krainer, C.E. Jefford, F. Bertoni, R. Zeillinger, and I. Irminger-Finger. 2007b. Oncogenic BARD1 isoforms expressed in gynecological cancers. Cancer Res 67: 11876-85.
[10]  Zhang YQ, Bianco A, Malkinson AM, Leoni VP, Frau G, De Rosa N, André PA, Versace R, Boulvain M, Laurent GJ, Atzori L, Irminger-Finger I. 2012. BARD1: an independent predictor of survival in non-small cell lung cancer. Int J Cancer. 131(1):83-94.
[11] Zhang YQ, Pilyugin M, Kuester D, Leoni VP, Li L, Casula G, Zorcolo L, Schneider-Stock R, Atzori L, Irminger-Finger I.. 2012. Expression of oncogenic BARD1 isoforms affects colon cancer progression and correlates with clinical outcome. Br J Cancer 107:675-83.$
[12] Lepore I, Dell’Aversana D, Pilyugin M, Conte M, Nebbioso A, De Bellis F, Tambaro FP, Izzo T, Garcia-Manero G, Ferrara F, Irminger-Finger I, and Altucci I.  HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b. PlosONE 2013, 8(12): e83018.
[13] Nowakowska B, et al. & Irminger-Finger I, Limon J, and Kozlow P. Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example. Sci Rep. 2015 May 21;5:10424.
[14] Ratajska M, Matusiak M, Kuzniacka A, Wasag B, Brozek I, Biernat W, Koczkowska M, Debniak J, Sniadecki M, Kozlowski P, Klonowska K, Pilyugin M, Wydra D, Laurent G, Limon J, Irminger-Finger I. Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms. Oncol Rep. 2015 Nov;34(5):2609-17.