The breast cancer susceptibility gene BRCA1

The BRCA1 gene on chromosome 17 at q21.1
consists of 24 exons spanning 80 kb of genomic
DNA that encode a 7.8 kb mRNA transcript. The
protein has 1863 amino acids. Exon 11 is quite
large (3.4 kb). About 55% of all mutations occur
in exon 11. Although some mutations occur
relatively frequently in other exons, they tend to
be evenly distributed throughout the gene (only
some mutations are shown). The deletion of an
adenine (A) and a guanine (G) in nucleotide
position 185 (185delAG) and the insertion of a
cytosine in position 5382 (5382insC) account
for about 10% of mutations each. These mutations
are particularly frequent in the Ashkenazi
Jewish population.
The protein has five main functional domains.
The RING finger region near the N-terminus at
amino acids 1–112 defines a zinc-binding
domain of conserved cysteine and histidine residues
that mediate protein—protein or protein-
DNA interactions. This region is also the site of
heterodimerization of BRCA1 and BARD1
(BRCA1-associated RING domain 1). Other
functional domains define the central part of
the BRCA1 protein. These are two nuclear localization
signals (NLS) and two protein-binding
domains, one for p53 protein, retinoblastoma
(RB) protein, and RAD50 and RAD51. RAD50 and
51 are proteins involved in recombination
during mitosis and meiosis, and in recombinational
repair of double-stranded DNA breaks.
The C-terminus contains a region involved in
transcriptional activation and DNA repair.