BRCA2
Proteins

Author: Roberta Vinella
Date: 31/08/2013

Description

DEFINITION

BRCA2 (BReast CAncer type 2 susceptibility protein) in humans is encoded by the breast cancer susceptibility gene that is a tumor suppressor gene (Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage, 2004).

THE GENE

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3). This gene is composed of 27 exons and encodes a predicted 384-kDa (The BRCA2 gene product functionally interacts with p53 and RAD51, 1998).

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WikigenesBRCA2
GeneCardsBRCA2
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iHOPBRCA2
OMIMBRCA2

CHEMICAL STRUCTURE AND IMAGES

The BRCA2 gene encodes a nuclear phosphoprotein of 3418 amino acids. Sequence analysis has revealed that its exon 3-encoded region shares some sequence similarity with the transactivation domain present in c-Jun, and functional analysis has confirmed the presence of an inherent transactivation function within this region. A prominent architectural feature resident within the BRCA2 primary amino acid sequence comprises eight tandem copies of a repetitive sequence motif termed the BRC repeat. Each BRC repeat, designated BRC1 to BRC8, is approximately 30 amino acids in length. Among the eight BRC repeats within BRCA2, the sequences of six are highly conserved among the repeats and can mediate the interaction of BRCA2 with RAD51. The two remaining repeats, BRC5 and BRC6, are less conserved and do not bind to RAD51. A third notable region within the BRCA2 primary amino acid sequence, spanning residues 2472 to 2957, represents a region of higher sequence conservation between human and mouse BRCA2 than the coding sequence as a whole. An evolutionarily conserved protein, DSS1, has been found to interact with BRCA2 in this region, although the significance of this interaction is not clear (Lessons learned from BRCA1 and BRCA2, 2000).

Protein Aminoacids Percentage

CELLULAR FUNCTIONS

BRCA2 in transcriptional regulation

The role of BRCA2 in transcriptional regulation is supported by several lines of evidence:

  • The product of BRCA2 exon 3 (amino acids 23-105), when fused to DNA-binding domains, activates transcription and that a missense mutation (Tyr42Cys) of BRCA2 reduces the transactivation potential.
  • Overexpression of BRCA2 is associated with down-regulation of basal p53 transcriptional activity.
  • BRCA2 might activate transcription by modulating histone acetyltransferase activity and consistently, interacts with the transcription co-activator protein P/CAF (p300/CBP -associated factors). BRCA2 might recruit these histone modifiers to the transcription complex to induce transcriptional activity.
  • The protein EMSY binds to exon 3 of BRCA2. EMSY is amplified in some sporadic breast cancers and appears to negatively regulate BRCA2 function in transcriptional activation. A role for EMSY in the DNA damage response is supported by its co-localization with γ-H2AX and BRCA2 in irradiated cells. EMSY also has a basal promoter suppressive function, suggesting that it functions as a general transcriptional repressor. Moreover, EMSY is implicated in DNA repair and chromatin remodeling. In sporadic breast cancer, EMSY amplification correlates with a poorer outcome, specifically for node-negative breast cancer. In addition, overexpression of EMSY is associated with high-grade sporadic ovarian carcinomas, suggesting involvement of the BRCA2 pathway in sporadic breast and ovarian cancers.

(Lessons learned from BRCA1 and BRCA2, 2000; Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage, 2004).

BRCA2 in DNA repair

Interaction between BRCA2 and RAD51: The potential role of BRCA2 in DNA repair was revealed by identification of its interaction with human or mouse RAD51. Eukaryotic RAD51 protein, similar to RecA, has ATP-dependent DNA binding activity and multimerizes to form a nucleoprotein filament on single-stranded DNA. Furthermore, RAD51 can catalyze homologous DNA pairing and DNA strand exchange in an in vitro recombination reaction.
Multiple discrete regions in BRCA2, including six BRC repeats, mediate its interaction with RAD51. It is, therefore, tempting to hypothesize that BRCA2 may increase the efficiency for RAD51-nucleoprotein filament formation by binding multiple RAD51 subunits. Other protein components, such as a single-strand DNA binding protein, replication protein A, RAD52, and RAD55/RAD57 heterodimer are necessary for the formation of the RAD51-filament by enhancing the activity of RAD51. It is conceivable that BRCA2 is also required for the formation of the RAD51-filament and the proper function of RAD51. Consistent with this notion, IR-induced RAD51 formation diminished in BRCA2-deficient cells or in cells in which the interaction between BRCA2 and RAD51 is specifically disrupted. Therefore, BRCA2 appears to be necessary for the assembly of RAD51 complexes upon DNA damage (Lessons learned from BRCA1 and BRCA2, 2000).

Interaction between BRCA1 and BRCA2: BRCA1 and BRCA2 interact in vivo. A region adjacent to, but not at the extreme C-terminus of BRCA1 was shown to mediate this interaction. BRCA2 also localizes in nuclear dots in mitotic cells at S or G2 phase and, colocalizes with BRCA1 on synaptonemal complexes of meiotic chromosomes. The functional consequence of the interaction between BRCA1 and BRCA2 remains elusive, although it is possible that this interaction may be involved in coupling the functions RAD51 (Lessons learned from BRCA1 and BRCA2, 2000).

BRCA2 in DNA double strand breaks (DBSs) repair and in checkpoint control: The primary function of BRCA2 is to facilitate homologous recombination (HR). BRCA2-deficient cells are defective in recruiting RAD51 to sites of DSBs and in repairing DSBs by HR. Although human and mouse cells expressing a BRCA2 loss-of-function truncation mutant display some defects in replication and checkpoint control, BRCA2 is not essential for these processes. In addition to its role in repair by HR, the other role of BRCA2 is protecting the replication fork. The critical evidence supporting these two functions of BRCA2 was a dissociation-of-function mutant, S3291A, the expression of which allows normal DSB-induced HR but results in defective protection of replication forks. Without the dissociation-of-function mutant, the reduced length of the nascent strand after replication fork stalling could be secondary to deletions in the sister chromatid arising either from defective HR repair of the collapsed replication fork or from defective daughter-strand gap (DSG) repair by HR (BRCA1 and BRCA2: different roles in a common pathway of genome protection, 2011).

BRCA2 AND CANCER

Mutations in BRCA2 are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer.
While not homologous genes, BRCA2 have an unusually large exon 11 and translational start sites in exon 2. In tumors associated with BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.
Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA2. The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA2 is tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families (Genetics of Breast and Ovarian Cancer, 2013).

Population estimates of the likelihood of having BRCA2 mutation

  • Among the general population, the likelihood of having any BRCA mutation is as follows:
    • General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
    • Women with breast cancer (any age): 1 in 50 (2%).
    • Women with breast cancer (younger than 40 years): 1 in 10 (10%).
    • Men with breast cancer (any age): 1 in 20 (5%).
    • Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).
  • Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:
    • General Ashkenazi Jewish population: 1 in 40 (2.5%).
    • Women with breast cancer (any age): 1 in 10 (10%).
    • Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
    • Men with breast cancer (any age): 1 in 5 (19%).
    • Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).

(Genetics of Breast and Ovarian Cancer, 2013)

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