BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene. [5] [6] [7] The human BARD1 protein is 777 amino acids long and contains a RING finger domain (residues 46-90), four ankyrin repeats (residues 420-555), and a tandem BRCT domain (residues 568-777). [8] [9]
Most, if not all, BRCA1 heterodimerizes with BARD1 in vivo. [10] BARD1 and BRCA1 form a heterodimer via their N-terminal RING finger domains. The BARD1-BRCA1 interaction is observed in vivo and in vitro and is essential for BRCA1 stability. BARD1 shares homology with the two most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes, and developmentally important genes such as the polycomb group of genes. The BARD1 protein also contains three tandem ankyrin repeats. [9] [11] [12]
The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. BARD1 may be the target of oncogenic mutations in breast or ovarian cancer. [11] Mutations in the BARD1 protein that affect its structure appear in many breast, ovarian, and uterine cancers, suggesting the mutations disable BARD1's tumor suppressor function. [8] Three missense mutations, each affecting BARD1's BRCT domain, are known to be implicated in cancers: C645R is associated with breast and ovarian cancers, V695L is associated with breast cancer, and S761N is associated with breast and uterine cancers. [8] BARD1 expression is upregulated by genotoxic stress and involved in apoptosis through binding and stabilizing p53 independently of BRCA1. [13]
BARD1 is vital in the rapid relocation of BRCA1 to DNA damage sites. [14] BARD1 tandem BRCA1 C-terminus (BRCT) motifs fold into a binding pocket with a key lysine residue (K619), and bind to poly(ADP-ribose) (PAR), which targets the BRCA1/BARD1 heterodimer to damaged DNA sites. [14] Double stranded breaks (DSB) in DNA trigger poly(ADPribose) polymerase 1 (PARP1) to catalyze the formation of poly(ADPribose) (PAR) so that PAR can then bind to an array of DNA response proteins, including the BRCA1/BARD1 heterodimer, and target them to DNA damage sites. [15] When the BRCA1/BARD1 heterodimer is transported to the damaged DNA site, it acts as an E3 ubiquitin ligase. [10] The BRCA1/BARD1 heterodimer ubiquitinates RNA polymerase II, preventing the transcription of the damaged DNA, and restoring genetic stability. [16]
BRCA1/BARD1 appears to have an important function in the recruitment of RAD51 protein to DNA double-strand breaks which is a crucial early step in the homologous recombinational repair of these breaks. [17] It is likely that BRCA1/BARD1 functions as part of a higher-order “homologous recombination mediator complex” along with two other tumor suppressor proteins BRCA2 and PALB2. [17]
Additionally, the BRCA1/BARD1 heterodimer seems to antagonistically compete with the tumor suppressor 53BP1 to promote the homologous recombination pathway rather than non-homologous end joining during double-strand break repair. [18] Specifically, methylation of the H4K20 dimethylation mark (H4K20me2), found in large amounts in parental and unreplicated chromatin, supports 53BP1 recruitment. [19] However, in nascent chromosomes, where H4K20me2 is mostly diluted, H4K20me0-mediated recruitment of BRCA1/BARD1 increases, suggesting a role in cell-cycle-dependent DNA repair. [18]
BARD1 has been shown to interact with:
If a cancer cell's capacity to repair DNA damage were incapacitated, cancer treatments would be more effective. Inhibiting cancer cells' BRCA1/BARD1 heterodimer from relocating to DNA damage sites would induce tumor cell death rather than repair. One inhibition possibility is the BARD1 BRCT key lysine residue (K619). Inhibiting this lysine residue's ability to bind poly(ADP-ribose) would prevent the BRCA1/BARD1 heterodimer from localizing to DNA damage sites and subsequently prevent DNA damage repair. This would make cancer therapies such as chemotherapy and radiation vastly more effective. [33]
p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.
Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.
H2A histone family member X is a type of histone protein from the H2A family encoded by the H2AFX gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.
Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR, FANCS, FANCT, FANCU, FANCV, and probably FANCW. Fanconi anemia proteins, including FANCD2, are an emerging therapeutic target in cancer
Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.
Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).
Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.
Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.
Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.
Fanconi anemia group J protein is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene.
Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.
E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the SMURF2 gene which is located at chromosome 17q23.3-q24.1.
NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.
BRCA1 associated protein-1 is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.
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