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Gene Review

BARD1  -  BRCA1 associated RING domain 1

Homo sapiens

Synonyms: BARD-1, BRCA1-associated RING domain protein 1
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Disease relevance of BARD1


Psychiatry related information on BARD1

  • To support that the Bard could be considered a Renaissance neurologist, the following important neurological phenomena have been selected from his repertoire for discussion: tremors, paralysis and stroke, sleep disturbances, epilepsy, dementia, encephalopathies, and the neurology of syphilis [6].
  • C R Bard Nursing Award. Breast self-examination: the personal touch [7].

High impact information on BARD1

  • Given the suspected role of BRCA1/BARD1 in DNA repair, we tested whether inhibition of mRNA processing is linked to DNA damage [8].
  • The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression [8].
  • Supporting the physiological significance of these results, a previously identified tumor-associated germline mutation in BARD1 (Gln564His) reduced binding to CstF and abrogated inhibition of polyadenylation [8].
  • BARD1 and Rad51, two proteins associated with the BRCA1 dots, behaved similarly [9].
  • These results indicate that BARD1-mediated inhibition of polyadenylation may prevent inappropriate RNA processing during transcription, perhaps at sites of DNA repair, and they reveal an unanticipated integration of diverse nuclear events [10].

Chemical compound and disease context of BARD1

  • RT-PCR, performed on 10 ovarian cancers, revealed absence of the 5' portion of the BARD1 transcript in 7 tumors, and sequencing of the remaining 3 identified a missense mutation (A1291G) resulting in an amino acid change of glutamine 406 to arginine [4].
  • In this study we compared the efficacy of the hyaluronic acid (HA)-hyaluronidase (HAase), BTA-Stat (Bard/Bion Diagnostics, Redmond, Washington), Hemastix (Bayer Corp., Elkhart, Indiana) (hematuria detection) and UBC-Rapid (IDL Biotech, Borlänger, Sweden) tests, and cytology to detect bladder cancer [11].
  • In this report the authors review the results of a multicenter Phase I study in which they evaluated the safety and feasibility of using a new self-expanding nitinol stent, the Bard Memotherm, to treat CA stenosis [12].
  • The Groshong (Bard Access Systems, UT) catheter is a device with a unique three-position valve at its distal tip which eliminates the need for routine heparin flushing and minimizes the risk of venous air embolism [13].
  • OBJECTIVES.: This study evaluates the long-term clinical success of Durasphere (Carbon Metal Technologies, St. Paul, MN) compared with Contigen (C. R. Bard, Covington, GA) in the treatment of stress urinary incontinence caused by intrinsic sphincter deficiency (ISD) [14].

Biological context of BARD1

  • The BARD1-CstF-50 interaction inhibits polyadenylation in vitro [10].
  • Seven polymorphisms were detected within the 2.34 kb coding sequence of BARD1 . Somatically acquired missense mutations were observed in one breast carcinoma and one endometrial tumor; in at least one of these cases, tumor formation was accompanied by loss of the wild-type BARD1 allele, following the paradigm for known tumor suppressor genes [1].
  • It is not clear how the BRCA1-BARD1 ligase regulates various cellular processes such as DNA repair, cell-cycle progression, transcriptional regulation, and centrosome duplication [15].
  • We show that neither the homodimers nor the heterodimer displays affinity for nucleic acids, indicating that the proposed roles of BRCA1 and BARD1 in DNA repair and/or transcriptional activation must be mediated either by other regions of the proteins or by additional cofactors [16].
  • A mutational analysis by PCR-SSCP on the coding region and the exon-intron splice boundaries of the BARD1 gene yielded four different germline mutations [2].

Anatomical context of BARD1


Associations of BARD1 with chemical compounds

  • Deletion of the BRCA1 NH(2) terminus, which is bound by BARD1 as well as other proteins, eliminates >98% of BRCA1 association with the holo-pol [21].
  • The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin [22].
  • Moreover, we show that the cleavage site of BARD1 is located NH2 terminally but downstream of the RING domain essential for BARD1 and BRCA1 protein interaction [23].
  • This hydrolysis is inhibited by EGTA, and the calpain inhibitor I, N-acetyl-leu-leu-norleucinal, but not by several caspases inhibitors, suggesting that BARD1 is hydrolyzed by the calcium-dependent cysteine proteases, calpains [23].
  • Here we report on the structural consequences of such mutations introduced into the second Zn(2+) site (Site II) of the BRCA1 RING domain and their effect on the interaction with the BARD1 RING domain [24].

Physical interactions of BARD1

  • BRCA1 interacts with BARD1 to generate significant ubiquitin ligase activity which catalyzes nontraditional Lys-6-linked polyubiquitin chains [25].
  • NPM interacts with N-terminal fragments of BRCA1 and BARD1 in a manner dependent upon BRCA1-BARD1 heterodimer formation [15].

Enzymatic interactions of BARD1


Regulatory relationships of BARD1


Other interactions of BARD1

  • We analyzed the BARD1 gene in 40 families with hereditary breast and breast/ovarian cancer, tested negative for BRCA1 and BRCA2 mutations [2].
  • Two different mass spectrometry screens for protein ubiquitinated by BRCA1-BARD1 both identified NPM [15].
  • On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch-repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases [28].
  • Consistent with these data, repressing p53(Ser-15) phosphorylation by BRCA1-BARD1 depletion compromises p21 induction and the G(1)/S checkpoint arrest in response to IR but not UV radia-tion [29].
  • Using flow cytometry and 5-bromo-2-deoxyuridine incorporation assays, we discovered that transiently expressed BARD1 can elicit a p53-independent cell cycle arrest in G1 phase, and that this was abrogated by mutation of the BARD1 NLS but not by mutation of the nuclear export signal [30].

Analytical, diagnostic and therapeutic context of BARD1


  1. Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Thai, T.H., Du, F., Tsan, J.T., Jin, Y., Phung, A., Spillman, M.A., Massa, H.F., Muller, C.Y., Ashfaq, R., Mathis, J.M., Miller, D.S., Trask, B.J., Baer, R., Bowcock, A.M. Hum. Mol. Genet. (1998) [Pubmed]
  2. Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Ghimenti, C., Sensi, E., Presciuttini, S., Brunetti, I.M., Conte, P., Bevilacqua, G., Caligo, M.A. Genes Chromosomes Cancer (2002) [Pubmed]
  3. Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. Spahn, L., Petermann, R., Siligan, C., Schmid, J.A., Aryee, D.N., Kovar, H. Cancer Res. (2002) [Pubmed]
  4. Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. Wu, J.Y., Vlastos, A.T., Pelte, M.F., Caligo, M.A., Bianco, A., Krause, K.H., Laurent, G.J., Irminger-Finger, I. Int. J. Cancer (2006) [Pubmed]
  5. BARD1 translocation to mitochondria correlates with Bax oligomerization, loss of mitochondrial membrane potential, and apoptosis. Tembe, V., Henderson, B.R. J. Biol. Chem. (2007) [Pubmed]
  6. The neurology in Shakespeare. Fogan, L. Arch. Neurol. (1989) [Pubmed]
  7. C R Bard Nursing Award. Breast self-examination: the personal touch. Williams, K. Community outlook. (1979) [Pubmed]
  8. The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression. Kleiman, F.E., Manley, J.L. Cell (2001) [Pubmed]
  9. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Scully, R., Chen, J., Ochs, R.L., Keegan, K., Hoekstra, M., Feunteun, J., Livingston, D.M. Cell (1997) [Pubmed]
  10. Functional interaction of BRCA1-associated BARD1 with polyadenylation factor CstF-50. Kleiman, F.E., Manley, J.L. Science (1999) [Pubmed]
  11. A side by side comparison of cytology and biomarkers for bladder cancer detection. Schroeder, G.L., Lorenzo-Gomez, M.F., Hautmann, S.H., Friedrich, M.G., Ekici, S., Huland, H., Lokeshwar, V. J. Urol. (2004) [Pubmed]
  12. Multicenter study of the feasibility and safety of using the memotherm carotid arterial stent for extracranial carotid artery stenosis. Qureshi, A.I., Suri, M.F., New, G., Wadsworth, D.C., Dulin, J., Hopkins, L.N. J. Neurosurg. (2002) [Pubmed]
  13. Venous air embolism through a Groshong catheter. Waggoner, S.E. Gynecol. Oncol. (1993) [Pubmed]
  14. Long-term follow-up comparison of durasphere and contigen in the treatment of stress urinary incontinence. Andersen, R.C. Journal of lower genital tract disease. (2002) [Pubmed]
  15. Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase. Sato, K., Hayami, R., Wu, W., Nishikawa, T., Nishikawa, H., Okuda, Y., Ogata, H., Fukuda, M., Ohta, T. J. Biol. Chem. (2004) [Pubmed]
  16. Mapping the functional domains of BRCA1. Interaction of the ring finger domains of BRCA1 and BARD1. Meza, J.E., Brzovic, P.S., King, M.C., Klevit, R.E. J. Biol. Chem. (1999) [Pubmed]
  17. Repression of the putative tumor suppressor gene Bard1 or expression of Notch4(int-3) oncogene subvert the morphogenetic properties of mammary epithelial cells. Soriano, J.V., Irminger-Finger, I., Uyttendaele, H., Vaudan, G., Kitajewski, J., Sappino, A.P., Montesano, R. Adv. Exp. Med. Biol. (2000) [Pubmed]
  18. Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. Sauer, M.K., Andrulis, I.L. J. Med. Genet. (2005) [Pubmed]
  19. BRCA1-dependent and independent functions of BARD1. Irminger-Finger, I., Leung, W.C. Int. J. Biochem. Cell Biol. (2002) [Pubmed]
  20. BRCA1-independent ubiquitination of FANCD2. Vandenberg, C.J., Gergely, F., Ong, C.Y., Pace, P., Mallery, D.L., Hiom, K., Patel, K.J. Mol. Cell (2003) [Pubmed]
  21. The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. Chiba, N., Parvin, J.D. Cancer Res. (2002) [Pubmed]
  22. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. Wu-Baer, F., Lagrazon, K., Yuan, W., Baer, R. J. Biol. Chem. (2003) [Pubmed]
  23. Identification of an apoptotic cleavage product of BARD1 as an autoantigen: a potential factor in the antitumoral response mediated by apoptotic bodies. Gautier, F., Irminger-Finger, I., Grégoire, M., Meflah, K., Harb, J. Cancer Res. (2000) [Pubmed]
  24. BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions. Brzovic, P.S., Meza, J.E., King, M.C., Klevit, R.E. J. Biol. Chem. (2001) [Pubmed]
  25. Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. Hayami, R., Sato, K., Wu, W., Nishikawa, T., Hiroi, J., Ohtani-Kaneko, R., Fukuda, M., Ohta, T. Cancer Res. (2005) [Pubmed]
  26. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. Starita, L.M., Horwitz, A.A., Keogh, M.C., Ishioka, C., Parvin, J.D., Chiba, N. J. Biol. Chem. (2005) [Pubmed]
  27. Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1. Rodriguez, J.A., Schüchner, S., Au, W.W., Fabbro, M., Henderson, B.R. Oncogene (2004) [Pubmed]
  28. Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas. Yoshikawa, K., Ogawa, T., Baer, R., Hemmi, H., Honda, K., Yamauchi, A., Inamoto, T., Ko, K., Yazumi, S., Motoda, H., Kodama, H., Noguchi, S., Gazdar, A.F., Yamaoka, Y., Takahashi, R. Int. J. Cancer (2000) [Pubmed]
  29. BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. Fabbro, M., Savage, K., Hobson, K., Deans, A.J., Powell, S.N., McArthur, G.A., Khanna, K.K. J. Biol. Chem. (2004) [Pubmed]
  30. Nuclear targeting and cell cycle regulatory function of human BARD1. Schüchner, S., Tembe, V., Rodriguez, J.A., Henderson, B.R. J. Biol. Chem. (2005) [Pubmed]
  31. Hyperphosphorylation of the BARD1 tumor suppressor in mitotic cells. Choudhury, A.D., Xu, H., Modi, A.P., Zhang, W., Ludwig, T., Baer, R. J. Biol. Chem. (2005) [Pubmed]
  32. Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis. Huo, X., Hu, Z., Zhai, X., Wang, Y., Wang, S., Wang, X., Qin, J., Chen, W., Jin, G., Liu, J., Gao, J., Wei, Q., Wang, X., Shen, H. Breast Cancer Res. Treat. (2007) [Pubmed]
  33. Needle muscle biopsy with the automatic Biopty instrument. Coté, A.M., Jiménez, L., Adelman, L.S., Munsat, T.L. Neurology (1992) [Pubmed]
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