BRCA1, BRCA2 and their products

Last update: December 8, 2016

BRCA1, BRCA2 and their products
Both BRCA1 and BRCA2 are involved in maintenance of genome stability, as they are crucial for the process of DNA repair by homologous recombination (HRR), which is considered to be a conservative form of DNA repair, largely involved in repairing DNA lesions that stall DNA replication forks and/or cause DNA double-strand breaks.

Although there are many ostensibly distinct forms of HRR in eukaryotes, the canonical form requires BRCA2 to bind directly to the DNA recombinase RAD51 and then localize it to damaged DNA. In the absence of functional BRCA2, HRR is impaired. Although the localization of RAD51 is also impaired in BRCA1-mutant cells, the role of BRCA1 in DNA damage responses seems to be broader, with BRCA1 controlling the signal transduction processes involved in HRR, as well as determining whether DNA double-strand breaks are resected before RAD51 nucleoprotein formation.

BRCA1 is located on chromosome 17, chromosomal region 17q21.31. It contains 23 exons in its most frequent occuring isoform (mRNA reference sequence in RefSeqProject: NM_007294.3) and encodes a protein of 1863 amino acids (protein reference sequence in RefSeqProject: NP_009225.1). The encoded protein combines with other tumour suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).
The protein has four main domains: The RING zinc finger domain, two BRCT domains and the serine domain. At the amino terminal of the protein, a RING zinc finger domain is present which interacts with another RING domain containing protein called BARD1. The BRCA1/BARD1 complex carries E3 ligase activity which is responsible for ubiquitination. At the carboxyl terminal, there are 2 BRCT repeats which are considered to activate transcription of reporter genes. Moreover, the 2 BRCT repeats are not only thought to bind to phospho-peptides which participate in DNA repair and cell cycle check points but they also interact with other proteins like BACH1,CtIP, RAP80 and CCDC98.

BRCA2 is located on chromosome 13, chromosomal region 13q13.1. It contains 27 exons (mRNA reference sequence in RefSeqProject: NM_000059.3) and encodes a protein of 3418 amino acids (protein reference sequence in RefSeqProject: NP_000050.2).
There are eight copies of 30-80 amino acid repeat in a part of the protein which is coded by the unusually long exon 11. This repeat motif is the most striking characteristic of the BRCA2 protein and is present in the central third of the BRCA2 protein. It is termed as the BRC domain. This BRC domain serves as a binding site for Rad51. Another location on the BRCA2 protein which serves as a binding site for Rad51 is the carboxyl terminal region of BRCA2 termed TR2. This section of the protein is believed to play a significant role in recombination repair.

Because the wild-type BRCA allele is lost during tumourigenesis, they have been considered classic tumour suppressor genes.

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