BARD1 (BRCA1 associated RING domain 1)
Written | 2007-02 | Irmgard Irminger-Finger |
Biology of Aging Laboratory, Dept of Geriatrics, Dept of Gynecology, Obstetrics, Geneva University, University Hospitals, 30, Bloulevard de la Cluse, CH-1211 Geneva, Switzerland |
(Note : for Links provided by Atlas : click)
1. Identity
Other alias | General Information |
HGNC (Hugo) | BARD1 |
LocusID (NCBI) | 580 |
Atlas_Id | 756 |
Location | 2q35 [Link to chromosome band 2q35] |
Location_base_pair | Starts at 214725646 and ends at 214809711 bp from pter ( according to hg19-Feb_2009) [Mapping BARD1.png] |
Local_order | Antiparallel |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
BARD1 (2q35) / CASC4 (15q15.3) |
2. DNA/RNA
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BARD1 structure is presented with RING finger (green) ankyrin repeats (ANK, blue) and BRCT domains (red). Positions of introns (in) are indicated. Structures of splice variants are shown for BARD1beta from the rat (Feki et al., 2004), BARD1delta (Feki et al., 2005; Tsuzuki et al., 2006). | |
Description | The gene spans 81 kb, composed of 11 exons. Alternatively spliced isoforms are identified. Insert known isoforms: BARD1beta (rat testis) BARD1delta (rat ovarian cancer cells) BARD1delta (HeLa) BARD1delta (rat ovarian cancer cells) |
Transcription | Transcription start is 100 bp upstream of first ATG of the BARD1 ORF. There a two 3'ends reported and possibly two alternative polyadenylation sites. BARD1 is expressed in most proliferative tissues. Highest expression in testis and spleen. No expression the central nervous system. |
Pseudogene | No pseudogenes reported. |
3. Protein
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Mouse and human BARD1 protein sequences are shown schematically. RING finger domains (gren), Ankyrin repeats (ANK, blue), BRCT domains (red), nulear localization signals (light blue). Homology between human and mouse BARD1 is indicated in perentage of identical amino acids for structural regions. | |
Description | Human BARD1 777 amino acids ; Structural motifs: RING, 5 Ankyrin repeats, 2 BRCT domains |
Expression | In the mouse BARD1 is expressed in most proliferative tissues. Highest expression in testis and spleen, no expression in nervous system. During mouse development BARD1 is expressed in early embryogenesis and declines after day 9. |
Localisation | During S-phase BARD1 localizes to nuclear dots. Partially, BARD1 is also localized to the cytoplasm in response to stress. |
Function | BARD1 functions as heterodimer with BRCA1 as ubiquitin ligase. Several targets of the BARD1-BRCA1 ubiquitin ligase have been identified and suggest its implication in DNA repair, polyadenylation, cell cycle control, and mitosis. BARD1 acts as inducer of apoptosis, independently of BRCA1, by binding to p53, and by binding to the stress response kinase DNA-PK, facilitating p53 phosphorylation and stabilization. Thus BARD1 acts as signaling molecule from genotoxic stress towards p53-dependent apoptosis. |
Homology | BARD1 is homologous to BRCA1, regarding the N-terminal RING finger and the C-terminal BRCT domains. Weak homology between BARD1 and BRCA1 can be found throughout exon 1 to exon 4. and from exon 7 through exon 11, with conserved intron-exon junctions. |
4. Mutations
Note | Several mutations of BARD1 have been identified in breast and ovarian cancers. Three mutations have been reported associated with inherited predisposition to breast and ovarian cancer. |
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BARD1 mutations associated with cancer. Small mutations are not unambiguously identified as cancer causing mutations, long arrows red labeled mutations are accepted as cancer associated. Blue indication maps germ line mutations. Q406R, might be cancer associated. | |
Germinal | Germline mutations were reported for C557S and Q564H. |
Somatic | Several somatic mutation were reported in addition to C557S and Q564H: |
5. Implicated in
Note | |
Entity | Breast and/or ovarian cancer |
Note | Upregulated expression of truncated BARD1 in epithelial cancers. |
Prognosis | Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer. |
Cytogenetics | No determined |
Hybrid/Mutated Gene | Not determined |
Abnormal Protein | No fusion proteins reported |
Entity | Ovarian cancer |
Prognosis | Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer. |
Hybrid/Mutated Gene | No |
Abnormal Protein | No fusion proteins reported |
Entity | Lung cancer |
Prognosis | Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer. |
Hybrid/Mutated Gene | No |
Abnormal Protein | No fusion proteins reported |
6. Bibliography
Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein. |
Ayi TC, Tsan JT, Hwang LY, Bowcock AM, Baer R |
Oncogene. 1998 ; 17 (16) : 2143-2148. |
PMID 9798686 |
Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. |
Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE |
Nature structural biology. 2001 ; 8 (10) : 833-837. |
PMID 11573085 |
Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. |
Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ |
The Journal of biological chemistry. 2002 ; 277 (24) : 22085-22092. |
PMID 11927591 |
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. |
Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R |
Molecular cell. 1998 ; 2 (3) : 317-328. |
PMID 9774970 |
The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. |
Chiba N, Parvin JD |
Cancer research. 2002 ; 62 (15) : 4222-4228. |
PMID 12154023 |
Hyperphosphorylation of the BARD1 tumor suppressor in mitotic cells. |
Choudhury AD, Xu H, Modi AP, Zhang W, Ludwig T, Baer R |
The Journal of biological chemistry. 2005 ; 280 (26) : 24669-24679. |
PMID 15855157 |
The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators. |
Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A |
Oncogene. 1999 ; 18 (22) : 3316-3323. |
PMID 10362352 |
BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. |
Fabbro M, Rodriguez JA, Baer R, Henderson BR |
The Journal of biological chemistry. 2002 ; 277 (24) : 21315-21324. |
PMID 11925436 |
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 AJ, Powell SN, McArthur GA, Khanna KK |
The Journal of biological chemistry. 2004 ; 279 (30) : 31251-31258. |
PMID 15159397 |
BARD1 regulates BRCA1 apoptotic function by a mechanism involving nuclear retention. |
Fabbro M, Schuechner S, Au WW, Henderson BR |
Experimental cell research. 2004 ; 298 (2) : 661-673. |
PMID 15265711 |
BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. |
Feki A, Jefford CE, Berardi P, Wu JY, Cartier L, Krause KH, Irminger-Finger I |
Oncogene. 2005 ; 24 (23) : 3726-3736. |
PMID 15782130 |
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 research. 2000 ; 60 (24) : 6895-6900. |
PMID 11156388 |
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 IM, Conte P, Bevilacqua G, Caligo MA |
Genes, chromosomes & cancer. 2002 ; 33 (3) : 235-242. |
PMID 11807980 |
Role of nucleophosmin in embryonic development and tumorigenesis. |
Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, Pandolfi PP |
Nature. 2005 ; 437 (7055) : 147-153. |
PMID 16007073 |
The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. |
Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T |
The Journal of biological chemistry. 2001 ; 276 (18) : 14537-14540. |
PMID 11278247 |
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 research. 2005 ; 65 (1) : 6-10. |
PMID 15665273 |
Is there more to BARD1 than BRCA1? |
Irminger-Finger I, Jefford CE |
Nature reviews. Cancer. 2006 ; 6 (5) : 382-391. |
PMID 16633366 |
Mutational analysis of BARD1 in familial breast cancer patients in Japan. |
Ishitobi M, Miyoshi Y, Hasegawa S, Egawa C, Tamaki Y, Monden M, Noguchi S |
Cancer letters. 2003 ; 200 (1) : 1-7. |
PMID 14550946 |
Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity. |
Jefford CE, Feki A, Harb J, Krause KH, Irminger-Finger I |
Oncogene. 2004 ; 23 (20) : 3509-3520. |
PMID 15077185 |
The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. |
Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A, Walter JC, Livingston DM |
Cell. 2006 ; 127 (3) : 539-552. |
PMID 17081976 |
Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies. |
Karppinen SM, Barkardottir RB, Backenhorn K, Sydenham T, Syrjäkoski K, Schleutker J, Ikonen T, Pylkäs K, Rapakko K, Erkko H, Johannesdottir G, Gerdes AM, Thomassen M, Agnarsson BA, Grip M, Kallioniemi A, Kere J, Aaltonen LA, Arason A, M&oring;ller P, Kruse TA, Borg A, Winqvist R |
Journal of medical genetics. 2006 ; 43 (11) : 856-862. |
PMID 16825437 |
BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II. |
Kleiman FE, Wu-Baer F, Fonseca D, Kaneko S, Baer R, Manley JL |
Genes & development. 2005 ; 19 (10) : 1227-1237. |
PMID 15905410 |
Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells. |
Lu Y, Amleh A, Sun J, Jin X, McCullough SD, Baer R, Ren D, Li R, Hu Y |
Molecular endocrinology (Baltimore, Md.). 2007 ; 21 (3) : 651-663. |
PMID 17185394 |
Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. |
Mallery DL, Vandenberg CJ, Hiom K |
The EMBO journal. 2002 ; 21 (24) : 6755-6762. |
PMID 12485996 |
Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. |
McCarthy EE, Celebi JT, Baer R, Ludwig T |
Molecular and cellular biology. 2003 ; 23 (14) : 5056-5063. |
PMID 12832489 |
Identification of residues required for the interaction of BARD1 with BRCA1. |
Morris JR, Keep NH, Solomon E |
The Journal of biological chemistry. 2002 ; 277 (11) : 9382-9386. |
PMID 11773071 |
BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. |
Morris JR, Solomon E |
Human molecular genetics. 2004 ; 13 (8) : 807-817. |
PMID 14976165 |
E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. |
Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA, Dynlacht BD |
Genes & development. 2002 ; 16 (2) : 245-256. |
PMID 11799067 |
Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1. |
Rodriguez JA, Schüchner S, Au WW, Fabbro M, Henderson BR |
Oncogene. 2004 ; 23 (10) : 1809-1820. |
PMID 14647430 |
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 |
The Journal of biological chemistry. 2004 ; 279 (30) : 30919-30922. |
PMID 15184379 |
Nuclear targeting and cell cycle regulatory function of human BARD1. |
Schüchner S, Tembe V, Rodriguez JA, Henderson BR |
The Journal of biological chemistry. 2005 ; 280 (10) : 8855-8861. |
PMID 15632137 |
BRCA1 is a component of the RNA polymerase II holoenzyme. |
Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM, Parvin JD |
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (11) : 5605-5610. |
PMID 9159119 |
Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. |
Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM |
Cell. 1997 ; 90 (3) : 425-435. |
PMID 9267023 |
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 JA, Aryee DN, Kovar H |
Cancer research. 2002 ; 62 (16) : 4583-4587. |
PMID 12183411 |
The BARD1 Cys557Ser variant and breast cancer risk in Iceland. |
Stacey SN, Sulem P, Johannsson OT, Helgason A, Gudmundsson J, Kostic JP, Kristjansson K, Jonsdottir T, Sigurdsson H, Hrafnkelsson J, Johannsson J, Sveinsson T, Myrdal G, Grimsson HN, Bergthorsson JT, Amundadottir LT, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K |
PLoS medicine. 2006 ; 3 (7) : page e217. |
PMID 16768547 |
BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. |
Starita LM, Horwitz AA, Keogh MC, Ishioka C, Parvin JD, Chiba N |
The Journal of biological chemistry. 2005 ; 280 (26) : 24498-24505. |
PMID 15886201 |
Genetic steps of mammalian homologous repair with distinct mutagenic consequences. |
Stark JM, Pierce AJ, Oh J, Pastink A, Jasin M |
Molecular and cellular biology. 2004 ; 24 (21) : 9305-9316. |
PMID 15485900 |
Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. |
Thai TH, Du F, Tsan JT, Jin Y, Phung A, Spillman MA, Massa HF, Muller CY, Ashfaq R, Mathis JM, Miller DS, Trask BJ, Baer R, Bowcock AM |
Human molecular genetics. 1998 ; 7 (2) : 195-202. |
PMID 9425226 |
A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. |
Tsuzuki M, Wu W, Nishikawa H, Hayami R, Oyake D, Yabuki Y, Fukuda M, Ohta T |
Cancer letters. 2006 ; 233 (1) : 108-116. |
PMID 15878232 |
BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition. |
Vahteristo P, Syrjäkoski K, Heikkinen T, Eerola H, Aittomäki K, von Smitten K, Holli K, Blomqvist C, Kallioniemi OP, Nevanlinna H |
European journal of human genetics : EJHG. 2006 ; 14 (2) : 167-172. |
PMID 16333312 |
BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. |
Westermark UK, Reyngold M, Olshen AB, Baer R, Jasin M, Moynahan ME |
Molecular and cellular biology. 2003 ; 23 (21) : 7926-7936. |
PMID 14560035 |
Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. |
Wu JY, Vlastos AT, Pelte MF, Caligo MA, Bianco A, Krause KH, Laurent GJ, Irminger-Finger I |
International journal of cancer. Journal international du cancer. 2006 ; 118 (5) : 1215-1226. |
PMID 16152612 |
Identification of a RING protein that can interact in vivo with the BRCA1 gene product. |
Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R |
Nature genetics. 1996 ; 14 (4) : 430-440. |
PMID 8944023 |
7. Citation
This paper should be referenced as such : |
Irminger-Finger, I |
BARD1 (BRCA1 associated RING domain 1) |
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):173-176. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/BARD1ID756ch2q35.html |
8. Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
t(2;7)(q35;q21) GTPBP10/BARD1
|
Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
Hereditary breast cancer |
9. External links
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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