![]() Structural features of BRCA1īRCA1 is located on chromosome 17q21.3, spans approximately 80 kb of genomic DNA, and is composed of 24 coding exons. The remainder of this review will focus on the role of BRCA1 within these complexes and their functions, which contribute to the maintenance of genomic stability and carcinogenesis. Indeed, to date, over 100 distinct BRCA1 interacting proteins have been reported and it is assumed that, through these interactions, the ability of BRCA1 to act as a scaffold for the formation of multiple different protein complexes with different cellular functions underlies its role in a diverse array of cellular processes. Although the exact mechanistic role of BRCA1 in many of these processes remains to be defined, it is considered that BRCA1 carries out these diverse roles through its ability to interact with a wide range of different proteins. Subsequent to its identification, much attention has been focused on understanding the function of BRCA1, with roles identified in multiple cellular processes required for maintaining genomic integrity, including DNA damage signaling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodeling, transcriptional regulation, mRNA splicing and apoptosis. The most striking phenotype of BRCA1 deficient cells is severe genomic instability and sensitivity to genotoxic agents, with BRCA1 deficient cells often exhibiting chromosomal translocations incorporating large deletions and/or amplifications that involve multiple, nonhomologous chromosomes. In addition, hypermethylation of BRCA1 promoters and loss of BRCA1 transcript has also been found in a significant proportion of sporadic breast and ovarian tumours. Additionally, although BRCA1/2 mutations account for a relatively low proportion of breast cancer cases as a whole, it has been found that between 50% and 70% of sporadic breast tumours have lost at least one BRCA1 allele, suggesting that the loss of BRCA1 may also be important for sporadic breast cancer development. Moreover, carriers of mutations within BRCA1 or BRCA2 have a life time risk of developing breast cancer of up to 60–80% and a lifetime risk of ovarian cancer of up to 20–40%. To date, over 800 distinct and clinically relevant mutations have been identified within the BRCA1 gene and, taken together, mutations within BRCA1 and BRCA2 may account for up to 20% of inherited breast cancer cases. In 1994, the first breast and ovarian cancer susceptibility gene, BRCA1, was identified and cloned, followed closely by the discovery of BRCA2 in 1995. Approximately 10% of women diagnosed with breast cancer report a strong family history, prompting the search for breast cancer susceptibility genes. ![]()
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