Search results for BARD1

Showing 23 results out of 56

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Protein (4 results from a total of 13)

Identifier: R-HSA-5659775
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BARD1: Q99728
Identifier: R-HSA-9699126
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BARD1: Q99728
Identifier: R-HSA-9700808
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BARD1: Q99728
Identifier: R-HSA-9699139
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: BARD1: Q99728

Interactor (2 results from a total of 2)

Identifier: Q99728-1
Species: Homo sapiens
Primary external reference: UniProt: Q99728-1
Identifier: A0AVN2
Species: Homo sapiens
Primary external reference: UniProt: A0AVN2

Reaction (4 results from a total of 13)

Identifier: R-HSA-5659781
Species: Homo sapiens
Compartment: nucleoplasm
BRCA1 and BARD1 form a stable heterodimer through an interaction between sequences encompassing their N-terminal RING domains (Wu et al. 1996, Brzovic et al. 2001). In addition to the RING domains, BRCA1 and BARD1 both have tandem BRCT motifs at their C termini. The central region of BARD1 contains ankyrin repeats (Wu et al. 1996). Formation of BRCA1:BARD1 heterodimers is necessary for the repair of double-strand DNA breaks by homologous recombination (Westermark et al. 2003, Laufer et al. 2007), BRCA1-mediated tumor suppression (Shakya et al. 2008) and normal development (McCarthy et al. 2003). Tumorigenic BRCA1 mutations that abolish the formation of BRCA1:BARD1 heterodimers have been reported (Wu et al. 1996, Brzovic et al. 2001).
Identifier: R-HSA-9699163
Species: Homo sapiens
Compartment: nucleoplasm
The N-terminal RING domain and C-terminal BRCT repeats of BARD1 contribute to its binding to BRCA1 (Simons et al. 2006). While not frequently reported in cancer, missense mutations in these two regions of BARD1 affect BARD1 function in homology directed repair (HDR) by impairing its interaction with BRCA1 and may potentially contribute to hereditary breast and ovarian cancer (Lee et al. 2015).

The following BARD1 missense mutants have been reported in hereditary breast and ovarian cancer and shown to be impaired in their interaction with BRCA1 and in HDR:
BARD1 C53W (Lee et al. 2015; the C53W substitution produces an insoluble BARD1 protein)
BARD1 C71Y (Morris et al. 2002; Lee et al. 2015; the C71Y substitution produces an insoluble BARD1 protein)
BARD1 G623E (Lee et al. 2015).

The following BARD1 mutants impaired in their ability to bind to BRCA1 have been clinically reported but not in cancer samples and are annotated as candidates:

BARD1 W34R (Lee et al. 2015 - studied as a synthetic mutant, but is in ClinGen Allele Registry, Pawliczek et al. 2018)
BARD1 L44R (Morris et al. 2002, Lee et al. 2015 - studied as a synthetic mutant, but is in ClinGen Allele Registry, Pawliczek et al. 2018)
BARD1 C50G (Xia et al. 2003)
BARD1 C83G (Xia et al. 2003)

The following BARD1 mutants reported in cancer and predicted to be pathogenic have not been tested for their ability to bind to BRCA1 but share sequence similarity with functionally characterized BARD1 mutants:
BARD1 H68Y (similar to functionally characterized synthetic mutant BARD1 H68A, described in Xia et al. 2003)
BARD1 G632W (similar to functionally characterized cancer mutant BARD1 G623E, described in Lee et al. 2015).
Identifier: R-HSA-9663194
Species: Homo sapiens
Compartment: nucleoplasm
The heterodimerization of BRCA1 and BARD1 is mediated by sequences encompassing the N-terminal RING domains of both proteins (Wu et al. 1996, Brzovic, Rajagopal et al. 2001, Brzovic, Meza et al. 2001, Morris et al. 2002). Cancer-predisposing mutations in the RING domain of BRCA1 frequently disrupt the formation of the BRCA1:BARD1 complex.

The following BRCA1 mutants identified in cancer patients or in families with the hereditary breast and ovarian cancer syndrome were functionally tested and shown to be unable to bind to BARD1:
BRCA1 M18T (Ransburgh et al. 2010)
BRCA1 C24R (Ransburgh et al. 2010)
BRCA1 C27A (Ransburgh et al. 2010)
BRCA1 T37R (Ransburgh et al. 2010)
BRCA1 C39Y (Ransburgh et al. 2010)
BRCA1 H41A (Ransburgh et al. 2010)
BRCA1 H41R (Ransburgh et al. 2010)
BRCA1 C44F (Ransburgh et al. 2010)
BRCA1 C47G (Ransburgh et al. 2010)
BRCA1 C61G (Wu et al. 1996, Ransburgh et al. 2010)
BRCA1 C64G (Wu et al. 1996, Ransburgh et al. 2010)
BRCA1 C64R (Caleca et al. 2014).

The following BRCA1 mutants were identified in cancer and predicted to be pathogenic. They are annotated as candidate mutants for BARD1 binding deficiency based on sequence similarity with the functionally characterized missense mutants (the same amino acid residue affected by a missense mutation as in a missense mutant shown to be unable to bind to BARD1) or based on the truncation of the RING domain due to frameshift mutations:
BRCA1 C24F
BRCA1 H41Q
BRCA1 C61Y
BRCA1 Q12Tfs*5
BRCA1 E23Afs*18
BRCA1 E23Rfs*18
BRCA1 E23Vfs*17
Identifier: R-HSA-9701000
Species: Homo sapiens
Compartment: nucleoplasm
In vivo, most BRCA1 and BARD1 polypeptides exist in the form of the BRCA1:BARD1 heterodimer. Although BRCA1 and BARD1 each harbor a RING domain (Miki et al. 1994; Wu et al. 1996), only the RING domain of BRCA1 is known to associate functionally with E2 ubiquitin conjugating enzymes (Brzovic et al. 2001). In vitro, BRCA1 alone exhibits a residual E3 ligase activity that is dramatically enhanced upon heterodimerization with BARD1 (Hashizume et al. 2001, Chen et al. 2002, Mallery et al. 2002, Wu-Baer et al. 2003, Xia et al. 2003). In addition to extensive auto-polyubiquitination on multiple unidentified lysine residues of both BRCA1 and BARD1, the heterodimer also mono- and/or poly-ubiquitinates a number of other substrates, including the H2A histones (Ohta et al. 2011, Kalb et al. 2014). Depending on the associated E2 conjugase, BRCA1:BARD1 can generate polyubiquitin chains of various linkages, including K6-linked ubiquitin polymers, that are not typically involved in proteasomal degradation (Wu-Baer et al. 2003, Nishikawa et al. 2004, Christensen et al. 2007). Autoubiquitination has been reported to increase the enzymatic activity of the BRCA1:BARD1 complex and may promote DNA damage response signaling (Mallery et al. 2002). In contrast, its E3 ligase activity can be suppressed by association with regulatory factors such as the BAP1 ubiquitin hydrolase (Nishikawa et al. 2009) or the UBXN1 ubiquitin-binding protein (Wu-Baer et al. 2010). The cancer-predisposing BRCA1 missense mutation C61G prevents binding to BARD1 and thereby impairs the ubiquitin ligase activity of BRCA1 (Wu et al. 1996, Ransburgh et al. 2010, Brzovic et al. 2001, Mallery et al. 2002, Wu-Baer et al. 2003). Studies in mouse cells have shown that the ubiquitin ligase activity of BRCA1 is not essential for its role in tumor suppression (Shakya et al. 2011) or double-strand DNA break repair by homologous recombination.

Set (4 results from a total of 5)

Identifier: R-HSA-9699130
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9707070
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9663193
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9707299
Species: Homo sapiens
Compartment: nucleoplasm

Complex (4 results from a total of 14)

Identifier: R-HSA-5659802
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5690771
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-9701007
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5683809
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (4 results from a total of 8)

Identifier: R-HSA-9699150
Species: Homo sapiens
Although germline mutations of BARD1 are implicated in some cases of hereditary breast and ovarian cancer (HBOC), they occur less frequently that those of the BRCA1 or BRCA2 genes (De Brakeleer et al. 2010, Alenezi et al. 2020). From animal studies, it is known that the loss of BARD1 function results in a phenotype very similar to that caused by loss of BRCA1 function, characterized by embryonic lethality (McCarthy et al. 2003), genomic instability (McCarthy et al. 2003) and defects in homology-directed repair (Lee et al. 2015). A small number of clinically-relevant BARD1 missense mutants that have been functionally characterized and shown to be impaired in BRCA1 binding (Xia et al. 2003, Lee et al. 2015) are annotated in this pathway.
Identifier: R-HSA-5693565
Species: Homo sapiens
Compartment: nucleoplasm
Activated ATM phosphorylates a number of proteins involved in the DNA damage checkpoint and DNA repair (Thompson and Schild 2002, Ciccia and Elledge 2010), thereby triggering and coordinating accumulation of DNA DSB repair proteins in nuclear foci known as ionizing radiation-induced foci (IRIF). While IRIFs include chromatin regions kilobases away from the actual DSB site, this Reactome pathway represents simplified foci and events that happen proximal to the DNA DSB ends. In general, proteins localizing to the nuclear foci in response to ATM signaling are cooperatively retained at the DNA DSB site, forming a positive feedback loop and amplifying DNA damage response (Soutoglou and Misteli 2008).

Activated ATM phosphorylates the NBN (NBS1) subunit of the MRN complex (MRE11A:RAD50:NBN) (Gatei et al. 2000), as well as the nucleosome histone H2AFX (H2AX) on serine residue S139, producing gamma-H2AFX (gamma-H2AX) containing nucleosomes (Rogakou et al. 1998, Burma et al. 2001). H2AFX is phosphorylated on tyrosine 142 (Y142) under basal conditions (Xiao et al. 2009). After ATM-mediated phosphorylation of H2AFX on S139, tyrosine Y142 has to be dephosphorylated by EYA family phosphatases in order for the DNA repair to proceed and to avoid apoptosis induced by DNA DSBs (Cook et al. 2009). Gamma-H2AFX recruits MDC1 to DNA DSBs (Stucki et al. 2005). After ATM phosphorylates MDC1 (Liu et al. 2012), the MRN complex, gamma-H2AFX nucleosomes, and MDC1 serve as a core of the nuclear focus and a platform for the recruitment of other proteins involved in DNA damage signaling and repair (Lukas et al. 2004, Soutoglou and Misteli 2008).

RNF8 ubiquitin ligase binds phosphorylated MDC1 (Kolas et al. 2007) and, in cooperation with HERC2 and RNF168 (Bekker-Jensen et al. 2010, Campbell et al. 2012), ubiquitinates H2AFX (Mailand et al. 2007, Huen et al. 2007, Stewart et al. 2009, Doil et al. 2009) and histone demethylases KDM4A and KDM4B (Mallette et al. 2012).

Ubiquitinated gamma-H2AFX recruits UIMC1 (RAP80), promoting the assembly of the BRCA1-A complex at DNA DSBs. The BRCA1-A complex consists of RAP80, FAM175A (Abraxas), BRCA1:BARD1 heterodimer, BRCC3 (BRCC36), BRE (BRCC45) and BABAM1 (MERIT40, NBA1) (Wang et al. 2007, Wang and Elledge 2007)

Ubiquitin mediated degradation of KDM4A and KDM4B allows TP53BP1 (53BP1) to associate with histone H4 dimethylated on lysine K21 (H4K20Me2 mark) by WHSC1 at DNA DSB sites (Pei et al. 2011).

Once recruited to DNA DSBs, both BRCA1:BARD1 heterodimers and TP53BP1 are phosphorylated by ATM (Cortez et al. 1999, Gatei et al. 2000, Kim et al. 2006, Jowsey et al. 2007), which triggers recruitment and activation of CHEK2 (Chk2, Cds1) (Wang et al. 2002, Wilson and Stern 2008, Melchionna et al. 2000).

Depending on the cell cycle stage, BRCA1 and TP53BP1 competitively promote either homology directed repair (HDR) or nonhomologous end joining (NHEJ) of DNA DSBs. HDR through homologous recombination repair (HRR) or single strand annealing (SSA) is promoted by BRCA1 in association with RBBP8 (CtIP), while NHEJ is promoted by TP53BP1 in association with RIF1 (Escribano-Diaz et al. 2013).

Identifier: R-HSA-9675136
Species: Homo sapiens
Diseases of DNA double-strand break repair (DSBR) are caused by mutations in genes involved in repair of double strand breaks (DSBs), one of the most cytotoxic types of DNA damage. Unrepaired DSBs can lead to cell death, cellular senescence, or malignant transformation.

Germline mutations in DSBR genes are responsible for several developmental disorders associated with increased predisposition to cancer:
Ataxia telangiectasia, characterized by cerebellar neurodegeneration, hematologic malignancies and immunodeficiency, is usually caused by germline mutations in the ATM gene;
Nijmegen breakage syndrome 1, characterized by microcephaly, short stature and recurrent infections, is caused by germline mutations in the NBN (NBS1) gene;
Seckel syndrome, characterized by short stature, skeletal deformities and microcephaly, is caused by germline mutations in the ATR or RBBP8 (CtIP) genes.

Heterozygous germline mutations in BRCA1, BRCA2 or PALB2 cause the hereditary breast and ovarian cancer syndrome (HBOC), while homozygous germline mutations in BRCA2 and PALB2 cause Fanconi anemia, a developmental disorder characterized by short stature, microcephaly, skeletal defects, bone marrow failure, and predisposition to cancer.

Somatic mutations in DSBR genes are also frequently found in sporadic cancers.

The pathways "Defective DNA double strand break response due to BRCA1 loss of function" describes defects in DSB response caused by loss-of-function mutations in BRCA1 which prevent the formation of the BRCA1:BARD1 complex.

The pathway "Defective DNA double strand break response due to BARD1 loss of function" describes defects in DSB response caused by loss-of-function mutations in BARD1, the heterodimerization partner of BRCA1, which prevent the formation of the BRCA1:BARD1 complex.

The pathway "Defective homologous recombination repair (HRR) due to BRCA1 loss of function" describes defects in HRR caused by loss-of-function mutations in BRCA1 that impair its association with PALB2.

The pathway "Defective homologous recombination repair (HRR) due to BRCA2 loss of function" describes defects in HRR caused by loss-of-function mutations in BRCA2 that impair either it association with SEM1 (DSS1), its translocation to the nucleus, its binding to RAD51, or its binding to PALB2.

The pathway "Defective homologous recombination repair (HRR) due to PALB2 loss of function" describes defects in HRR caused by loss-of-function mutations in PALB2 that impair its association with BRCA2/RAD51/RAD51C.

For review, please refer to McKinnon and Caldecott 2007, Keijzers et al. 2017, and Jachimowicz et al. 2019.
Identifier: R-HSA-9663199
Species: Homo sapiens
Germline mutations in the BRCA1 or BRCA2 tumor suppressor genes are implicated in up to 10% of breast cancers overall and 40% of familial breast cancers. Carriers of either BRCA1 or BRCA2 germline mutation are predisposed to hereditary breast and ovarian cancer (the HBOC syndrome), which is inherited in an autosomal dominant manner. Besides early onset breast and ovarian cancer, HBOC patients also have a modestly increased risk of developing other tumor types, including pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. The BRCA1 gene encodes a large protein of 1863 amino acids, which contains a RING finger domain at the N-terminus and two BRCT repeats at the C-terminus. The RING domain is responsible for heterodimerization with BARD1, which increases stability of BRCA1 and activates its E3 ubiquitin ligase activity. BRCA1 plays an important role in homology-directed repair of DNA double-strand breaks (DSBs). Brca1-null knockout mice die early during embryonic development and cells depleted of BRCA1 show genomic instability (reviewed by Roy et al. 2011). Cancer mutations that affect the RING domain of BRCA1 frequently result in the inability of BRCA1 to bind to BARD1 and participate in DNA DSB response (Wu et al. 1996, Ransburgh et al. 2010). Some mutations in the RING domain of BRCA1 were shown to affect the ubiquitin ligase activity of BRCA1 (Brzovic et al. 2001), but it is uncertain if the ubiquitin ligase activity is essential for the tumor suppressor role of BRCA1 (Shakya et al. 2011).

Icon (1 results from a total of 1)

Species: Homo sapiens
BRCA1-associated RING domain protein 1
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