BARD1 (BRCA1 associated RING domain 1)

2007-02-01   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

Identity

HGNC
BARD1
LOCATION
2q35
LOCUSID
580
ALIAS
-
FUSION GENES
Show Gene Fusions

DNA/RNA

Atlas Image
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

Atlas Image
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.
Atlas Image
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
No
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
No
Fusion protein
No fusion proteins reported

Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

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

Variants:

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

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000138376ENST00000260947Q99728
ENSG00000138376ENST00000421162C9IYG1
ENSG00000138376ENST00000432456C9J6M1
ENSG00000138376ENST00000455743F8WCG2
ENSG00000138376ENST00000613192A0A087X0C6
ENSG00000138376ENST00000613374F6MDI1
ENSG00000138376ENST00000613706A0A087X2H0
ENSG00000138376ENST00000617164Q99728
ENSG00000138376ENST00000619009A0A087WZ19
ENSG00000138376ENST00000620057Q99728
ENSG00000138376ENST00000650978A0A494C142

Expression (GTEx)

0
5
10
15
20
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

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Homologous recombinationKEGGhsa03440
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
DeubiquitinationREACTOMER-HSA-5688426
UCH proteinasesREACTOMER-HSA-5689603
Metalloprotease DUBsREACTOMER-HSA-5689901

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD30071039
PA448803carboplatinChemicalClinicalAnnotationassociatedPD30071039
PA449383docetaxelChemicalClinicalAnnotationassociatedPD30071039
PA451743trastuzumabChemicalClinicalAnnotationassociatedPD30071039

References

Pubmed IDYearTitleCitations
194121752009Common variations in BARD1 influence susceptibility to high-risk neuroblastoma.137
194121752009Common variations in BARD1 influence susceptibility to high-risk neuroblastoma.137
284184442017Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer.109
124859962002Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains.90
128906882003The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin.87
149761652004BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair.84
146386902004Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase.73
124319962003Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein.72
272397952016Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection.69
119275912002Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase.62

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/favicon/apple-touch-icon.png