Breast cancer type 1 susceptibility protein
EC=6.3.2.-
Alternative name(s):
RING finger protein 53
Function
Lys-6'-結合ポリユビキチン鎖の形成を特異的に仲介し、細胞のDNA傷害に対する反応を最適化することでDNA修復に重要な役割を果たすE3ユビキチンタンパク質リガーゼ。
ほかのタイプのポリユビキチン鎖の形成に関与するかどうかは不明。E3ユビキチンタンパク質リガーゼ活性はがん抑制機能に必要である。
E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function.
BRCA1-BARD1によるヘテロダイマーはゲノムの安定性を維持するうえでDNA傷害の修復、ユビキチン化と転写調節のような幅広い範囲の細胞の過程を調整する。微少管の結合やG2期からM期への以降などを調節する。S期、G2期の電離放射線被曝後の細胞周期の適切な停止に必要である。
The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle.
DNA傷害にともなうP21タンパク質の転写に関与する。
Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation.
PALB2との直接的な相互作用により、相同的組み換えによるDNA修復に寄与する。
Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Ref.13 Ref.16 Ref.24 Ref.26 Ref.27 Ref.29 Ref.30 Ref.34 Ref.35 Ref.37 Ref.41 Ref.45 Ref.48 Ref.50 Ref.51
Enzyme regulation
The E3 ubiquitin-protein ligase activity is inhibited by phosphorylation by AURKA. Activity is increased by phosphatase treatment. Ref.37
Pathway
Protein modification; protein ubiquitination.
Subunit structure
Heterodimer with BARD1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1, BRCC3, BRE and BABAM1. Interacts (via the BRCT domains) with FAM175A. Component of the BRCA1-RBBP8 complex. Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage. Associates with RNA polymerase II holoenzyme. Interacts with SMC1A and COBRA1. Interacts (via BRCT domains) with BRIP1 (phosphorylated form). Interacts with FANCD2 (ubiquitinated form). Interacts with BAP1. Interacts with DCLRE1C and CLSPN. Interacts with H2AFX (phosphorylated on 'Ser-140'). Interacts with CHEK1 and CHEK2. Interacts with BRCC3. Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA. Interacts with AURKA. Interacts with UBXN1. Part of a trimeric complex containing BRCA1, BRCA2 and PALB2. Interacts directly with PALB2; the interaction is essential for its function in HRR. Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein. Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1. Ref.11 Ref.12 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.28 Ref.29 Ref.30 Ref.31 Ref.32 Ref.34 Ref.35 Ref.36 Ref.38 Ref.39 Ref.41 Ref.48 Ref.50 Ref.52 Ref.56 Ref.57 Ref.58
Subcellular location
Nucleus. Note: Localizes at sites of DNA damage at double-strand breaks (DSBs); recruitment to DNA damage sites is mediated by the BRCA1-A complex. Ref.3 Ref.10 Ref.11 Ref.41 Ref.56
Isoform 3: Cytoplasm Ref.3 Ref.10 Ref.11 Ref.41 Ref.56.
Isoform 5: Cytoplasm Ref.3 Ref.10 Ref.11 Ref.41 Ref.56.
Tissue specificity
Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines. Ref.3
Domain
The BRCT domains recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of FAM175A/Abraxas, recruits BRCA1 at DNA damage sites. Ref.60
The RING-type zinc finger domain interacts with BAP1. Ref.60
Post-translational modification
Phosphorylation at Ser-308 by AURKA is required for normal cell cycle progression from G2 to mitosis. Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR. Phosphorylation at Ser-988 by CHEK2 regulates mitotic spindle assembly. Ref.15 Ref.16 Ref.20 Ref.30 Ref.33 Ref.37 Ref.40 Ref.43 Ref.44 Ref.49 Ref.51
Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.
Polymorphism
There is evidence that the presence of the rare form of Gln-356-Arg and Leu-871-Pro polymorphisms may be associated with an increased risk for developing ovarian cancer.
Involvement in disease
Defects in BRCA1 are a cause of susceptibility to breast cancer (BC) [MIM:114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=Mutations in BRCA1 are thought to be responsible for 45% of inherited breast cancer. Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3-fold increased risk of prostate cancer. Cells lacking BRCA1 show defects in DNA repair by homologous recombination. Ref.1 Ref.17 Ref.54 Ref.56 Ref.59 Ref.62 Ref.63 Ref.64 Ref.65 Ref.67 Ref.68 Ref.69 Ref.70 Ref.71 Ref.73 Ref.77 Ref.78 Ref.81
Defects in BRCA1 are a cause of susceptibility to familial breast-ovarian cancer type 1 (BROVCA1) [MIM:604370]. A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. Note=Mutations in BRCA1 are thought to be responsible for more than 80% of inherited breast-ovarian cancer.
Defects in BRCA1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000]. The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.
Defects in BRCA1 are a cause of susceptibility to pancreatic cancer type 4 (PNCA4) [MIM:614320]. A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
Sequence similarities
Contains 2 BRCT domains.
Contains 1 RING-type zinc finger.
