Breast cancer type 2 susceptibility protein
Function
DNA二本鎖切断の修復および相同的組換えに関与する。RAD51と結合し一本鎖DNA上でRAD51の構成を促し組換えによるDNAの修復過程を促進する。
Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Ref.6 Ref.7 Ref.10 Ref.16 Ref.18 Ref.19 Ref.20 Ref.21 Ref.24
Subunit structure
単量体、または二量体として、RAD51と相互作用し、DNA修復部位にRAD51を導き調節する。BACA1、BRCA2にPALB2を不腔BRCA複合体の一部である。
Monomer and dimer. Interacts with RAD51; regulates RAD51 recruitment and function at sites of DNA repair. Interacts with DSS1, WDR16, USP11, DMC1, ROCK2 and NPM1. Interacts with both nonubiquitinated and monoubiquitinated FANCD2; this complex also includes XRCC3 and phosphorylated FANCG. Interacts with WDR16. Part of a BRCA complex containing BRCA1, BRCA2 and PALB2. Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3. Interacts with BRCA1 only in the presence of PALB2 which serves as the bridging protein. Interacts with POLH; the interaction is direct. Ref.6 Ref.7 Ref.8 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.23 Ref.24
Subcellular location
Nucleus Probable. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome Ref.22.
Tissue specificity
Highest levels of expression in breast and thymus, with slightly lower levels in lung, ovary and spleen.
Post-translational modification
Phosphorylated by ATM upon irradiation-induced DNA damage. Phosphorylation by CHEK1 and CHEK2 regulates interaction with RAD51. Phosphorylation at Ser-3291 by CDK1 and CDK2 is low in S phase when recombination is active, but increases as cells progress towards mitosis; this phosphorylation prevents homologous recombination-dependent repair during S phase and G2 by inhibiting RAD51 binding. Ref.7 Ref.11 Ref.16
Ubiquitinated in the absence of DNA damage; this does not lead to proteasomal degradation. In contrast, ubiquitination in response to DNA damage leads to proteasomal degradation. Ref.8
Involvement in disease
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: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.13 Ref.31 Ref.32 Ref.33 Ref.34 Ref.37 Ref.38 Ref.40 Ref.41 Ref.42 Ref.43 Ref.45 Ref.50 Ref.51 Ref.52 Ref.55 Ref.59 Ref.60 Ref.62 Ref.64
Pancreatic cancer 2 (PNCA2) [MIM:613347]: 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5
Breast-ovarian cancer, familial, 2 (BROVCA2) [MIM:612555]: 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: Disease susceptibility is associated with variations affecting the gene represented in this entry.
Fanconi anemia complementation group D1 (FANCD1) [MIM:605724]: A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.53 Ref.58 Ref.67
Glioma 3 (GLM3) [MIM:613029]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9
Sequence similarities
Contains 8 BRCA2 repeats.
