BARD1 (BRCA1 associated RING domain 1)

2007-02-01 Irmgard Irminger-Finger Affiliation

Biology of Aging Laboratory, Dept of Geriatrics, Dept of Gynecology, Obstetrics, Geneva University, University Hospitals, 30, Bloulevard de la Cluse, CH-1211 Geneva, Switzerland

Identity

HGNC

BARD1

LOCATION

2q35

LOCUSID

580

ALIAS

FUSION GENES

Show Gene Fusions

DNA/RNA

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 3ends 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.

Proteins

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.

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.

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:

Implicated in

Entity name

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 gene

Not determined

Fusion protein

No fusion proteins reported

Entity name

Ovarian cancer

Prognosis

Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer.

Hybrid gene

Fusion protein

No fusion proteins reported

Entity name

Lung cancer

Prognosis

Upregulated BARD1 is correlated with poor prognosis in breast and ovarian cancer.

Hybrid gene

Fusion protein

No fusion proteins reported

Article Bibliography

Pubmed ID	Last Year	Title	Authors
9798686	1998	Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein.	Ayi TC et al
11573085	2001	Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.	Brzovic PS et al
11927591	2002	Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase.	Chen A et al
9774970	1998	Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.	Chen J et al
12154023	2002	The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme.	Chiba N et al
15855157	2005	Hyperphosphorylation of the BARD1 tumor suppressor in mitotic cells.	Choudhury AD et al
10362352	1999	The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators.	Dechend R et al
11925436	2002	BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export.	Fabbro M et al
15159397	2004	BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage.	Fabbro M et al
15265711	2004	BARD1 regulates BRCA1 apoptotic function by a mechanism involving nuclear retention.	Fabbro M et al
15782130	2005	BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase.	Feki A et al
11156388	2000	Identification of an apoptotic cleavage product of BARD1 as an autoantigen: a potential factor in the antitumoral response mediated by apoptotic bodies.	Gautier F et al
11807980	2002	Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations.	Ghimenti C et al
16007073	2005	Role of nucleophosmin in embryonic development and tumorigenesis.	Grisendi S et al
11278247	2001	The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.	Hashizume R et al
15665273	2005	Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2.	Hayami R et al
16633366	2006	Is there more to BARD1 than BRCA1?	Irminger-Finger I et al
14550946	2003	Mutational analysis of BARD1 in familial breast cancer patients in Japan.	Ishitobi M et al
15077185	2004	Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity.	Jefford CE et al
17081976	2006	The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly.	Joukov V et al
16825437	2006	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 et al
15905410	2005	BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II.	Kleiman FE et al
17185394	2007	Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells.	Lu Y et al
12485996	2002	Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.	Mallery DL et al
12832489	2003	Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability.	McCarthy EE et al
11773071	2002	Identification of residues required for the interaction of BARD1 with BRCA1.	Morris JR et al
14976165	2004	BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair.	Morris JR et al
11799067	2002	E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.	Ren B et al
14647430	2004	Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1.	Rodriguez JA et al
15184379	2004	Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase.	Sato K et al
15632137	2005	Nuclear targeting and cell cycle regulatory function of human BARD1.	Schüchner S et al
9159119	1997	BRCA1 is a component of the RNA polymerase II holoenzyme.	Scully R et al
9267023	1997	Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage.	Scully R et al
12183411	2002	Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway.	Spahn L et al
16768547	2006	The BARD1 Cys557Ser variant and breast cancer risk in Iceland.	Stacey SN et al
15886201	2005	BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II.	Starita LM et al
15485900	2004	Genetic steps of mammalian homologous repair with distinct mutagenic consequences.	Stark JM et al
9425226	1998	Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers.	Thai TH et al
15878232	2006	A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats.	Tsuzuki M et al
16333312	2006	BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.	Vahteristo P et al
14560035	2003	BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks.	Westermark UK et al
16152612	2006	Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis.	Wu JY et al
8944023	1996	Identification of a RING protein that can interact in vivo with the BRCA1 gene product.	Wu LC et al

Other Information

Locus ID:

NCBI: 580
MIM: 601593
HGNC: 952
Ensembl: ENSG00000138376

Variants:

dbSNP: 580
ClinVar: 580
TCGA: ENSG00000138376
COSMIC: BARD1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000138376	ENST00000260947	Q99728
ENSG00000138376	ENST00000421162	C9IYG1
ENSG00000138376	ENST00000432456	C9J6M1
ENSG00000138376	ENST00000455743	F8WCG2
ENSG00000138376	ENST00000613192	A0A087X0C6
ENSG00000138376	ENST00000613374	F6MDI1
ENSG00000138376	ENST00000613706	A0A087X2H0
ENSG00000138376	ENST00000617164	Q99728
ENSG00000138376	ENST00000619009	A0A087WZ19
ENSG00000138376	ENST00000620057	Q99728
ENSG00000138376	ENST00000650978	A0A494C142

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Homologous recombination	KEGG	ko03440
Homologous recombination	KEGG	hsa03440
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
Cell Cycle	REACTOME	R-HSA-1640170
Cell Cycle Checkpoints	REACTOME	R-HSA-69620
G2/M Checkpoints	REACTOME	R-HSA-69481
G2/M DNA damage checkpoint	REACTOME	R-HSA-69473
DNA Repair	REACTOME	R-HSA-73894
DNA Double-Strand Break Repair	REACTOME	R-HSA-5693532
DNA Double Strand Break Response	REACTOME	R-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	REACTOME	R-HSA-5693565
Homology Directed Repair	REACTOME	R-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)	REACTOME	R-HSA-5693567
Processing of DNA double-strand break ends	REACTOME	R-HSA-5693607
HDR through Homologous Recombination (HRR)	REACTOME	R-HSA-5685942
Homologous DNA Pairing and Strand Exchange	REACTOME	R-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchange	REACTOME	R-HSA-5693616
Resolution of D-Loop Structures	REACTOME	R-HSA-5693537
Resolution of D-loop Structures through Holliday Junction Intermediates	REACTOME	R-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	REACTOME	R-HSA-5693554
HDR through Single Strand Annealing (SSA)	REACTOME	R-HSA-5685938
Nonhomologous End-Joining (NHEJ)	REACTOME	R-HSA-5693571
Regulation of TP53 Activity	REACTOME	R-HSA-5633007
Regulation of TP53 Activity through Phosphorylation	REACTOME	R-HSA-6804756
Deubiquitination	REACTOME	R-HSA-5688426
UCH proteinases	REACTOME	R-HSA-5689603
Metalloprotease DUBs	REACTOME	R-HSA-5689901

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA443560	Breast Neoplasms	Disease	ClinicalAnnotation	associated	PD	30071039
PA448803	carboplatin	Chemical	ClinicalAnnotation	associated	PD	30071039
PA449383	docetaxel	Chemical	ClinicalAnnotation	associated	PD	30071039
PA451743	trastuzumab	Chemical	ClinicalAnnotation	associated	PD	30071039

References

Pubmed ID	Year	Title	Citations
37418175	2024	Structural dynamics of clinically-reported VUS in the BARD1 ARD-BRCT region to predict the molecular basis of alterations.	0
37688570	2024	BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.	4
37688579	2024	Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.	2
38266639	2024	BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.	1
37418175	2024	Structural dynamics of clinically-reported VUS in the BARD1 ARD-BRCT region to predict the molecular basis of alterations.	0
37688570	2024	BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.	4
37688579	2024	Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.	2
38266639	2024	BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.	1
37561379	2023	Association of BARD1 and BRIP1 Gene Polymorphisms with the Risk of Uveal Melanoma.	1
37592023	2023	Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.	7
37823591	2023	BRCA1-BARD1 combines multiple chromatin recognition modules to bridge nascent nucleosomes.	2
37561379	2023	Association of BARD1 and BRIP1 Gene Polymorphisms with the Risk of Uveal Melanoma.	1
37592023	2023	Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.	7
37823591	2023	BRCA1-BARD1 combines multiple chromatin recognition modules to bridge nascent nucleosomes.	2
35203293	2022	RNAi Screening Uncovers a Synthetic Sick Interaction between CtIP and the BARD1 Tumor Suppressor.	0

Citation

Irmgard Irminger-Finger

BARD1 (BRCA1 associated RING domain 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/gene/756/cancer-prone-explorer/img/gene-fusions-explorer/