BRCA1 is termed as breast cancer susceptibility gene 1; it is the gene's official symbol. BRCA1 is human gene that belongs to a class of genes known as tumour suppressor genes. Its role is to stabilise DNA and prevent uncontrolled cell growth. BRCA proteins are involved in a great number of pivotal cellular processes. They act as regulators of DNA repair, transcription and cell cycle in response to DNA damage (Yoshida and Miki, 2004). The mutation of this gene has been linked to the predisposition of hereditary breast and ovarian cancer (NCI, 2009).
BRCA1 gene was discovered in 1994 (Gayther, et al., 1995) and mapped on human chromosome 17q21 (Russo et al., 2009). This 17q is characterized by autosomal dominant inheritance with incomplete penetrance. Loss of heterozygosity at 17q was found in most familial breast and ovarian tumours, suggesting the involvement of tumour suppressor genes (Neuhausen and Marshall, 1994; Smith et al., 1992). The BRCA1 gene acts as a tumour suppressor which plays a role in maintaining genomics stability, DNA repair, and cell cycle checkpoint control. BRCA1 forms a number of distinct complexes through association with different adaptor proteins and each complex forms in a mutually exclusive manner (Wang, et al., 2009).
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Figure : Structure of BRCA1 gene.
BRCA1 gene is composed of 24 exons, with an mRNA that is 7.8 kb in length and 22 coding exons translating into a protein of 1863 amino acids (Russo et al., 2009). The gene is large and spans approximately 80 kb of genomic DNA (Palma et al., 2006) with molecular weight of 220 kDa (Russo et al., 2009). The BRCA1 gene contains a RING finger domain near N-terminal, and BRCT domain at C-terminal. The interaction of protein-protein or protein-DNA transmission is maintained by cysteines and hystidines in which the RING finger is characterized zinc binding domains (Lovering et al., 1993). The RING finger of BRCA1 interact with BARD1 (BRCA1-associated RING domain protein 1) and perform an ubiquitin-ligase activity (Wu et al., 1996). The BRCT domain is an acidic C-terminal which consists of BRCA1 and BARD1. BRCA1, BARD1 and BRCT are homologous to each other (Bork et al., 1997). The BRCA1 contains two nuclear localization signals (NLSs) which located on exon 11. Exon 11 codifies 60% of protein and is extremely large.
The BRCA1 gene acts as human tumour suppressor genes. The BRCA 1 gene produces protein to prevent cells from growing and dividing in an uncontrolled way. BRCA1 protein interacts with proteins produced from RAD51 and BARD 1 genes to repair breaks in DNA. BARD1 interacts with the N-terminal region of BRCA1. BARD1 shares homology with N-terminal RING finger and C-terminal BRCT in order to bind BRCA1 in vivo and in vitro. The RING motif is a cysteine-rich sequence found in a variety of proteins. The cause of breakages in DNA occurs when chromosomes exchange genetic material in preparation for cell division. By helping repair DNA, BRCA1 plays a role in maintaining the stability of a cell's genetic information (GHR, 2007). The BRCA proteins have a nuclear localization, which plays a role in maintaining genomics stability, DNA repair, and cell cycle checkpoint control. BRCA1 forms a number of distinct complexes through association with different adaptor proteins and each complex forms in a mutually exclusive manner (Narod and Foulkes, 2004). BRCA1 gene is important to activate the cell cycle checkpoint kinase, which is the checkpoint pathways to control the order and timing of cell cycle transition, such as DNA replication and chromosome segregation (Karlsson et al., 1999).
BRCA1 and cancer
Inactivation of tumour suppressor gene is a key event in the development of cancer. BRCA1 is one of the most important tumour suppressor genes in the genome, and its mutations are found in approximately 75% families with hereditary ovarian cancers (Kasprzak et al., 1999). A mutated BRCA1 protein lacking two phophorylation sites, failed to rescue the radiation hypersensitivity of a BRCA1 deficient cell line. Thus, phosphorylation of BRCA1 by the checkpoint kinase ATM is very important for proper responses to DNA double-stand breaks (Cortez et al., 1999).
Figure 3: Localization of the human BRCA1 gene, chromosome 17q21. (http://www.bio.davidson.edu/COURSES/genomics/2002/Statler/BRCA.htm)
Mutations of BRCA1
Mutations in BRCA1 have been found throughout the entire splice sites and coding region. Splice site alterations, frameshift, or nonsense mutation are followed by small deletions or insertions of the majority of BRCA1 mutation genes which cause premature protein termination. The splice sties and coding region of BRCA1 gene were routinely screened for mutations lately (Mazoyer, 2005). A 6kb duplication of exon 13, ins6kbEx13, which creates a frameshift in the coding sequence, has been identified in the BRCA1 gene (Puget et al., 1999). There is approximately 40 to 53% of life time risk of ovarian cancer associated with BRCA1 mutation carriers (Ford et al., 1998) (Antoniou et al., 2002).
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Different BRCA1 mutations lead to different effects in normal ovarian tissues and differences in the biology of the translated protein. The penetrance can be influenced by low penetrance genes in the population. The evidence from several studies suggests that variations in disease risk that are observed are probably due to a combination of both of these factors. There is evidence that the location of mutations in BRCA1 can influence the risk of ovarian within families. An initial study suggested that mutations of BRCA1 located in the 5' end of the gene were associated with higher risks of ovarian cancer compared to mutations in the 3' end (Gayther et al., 1995).
Germline mutation in the BRCA 1 genes is characterized by deficient DNA double-strand break repair by homologous recombination (Murphy and Moynahan, 2010). Germline mutations of BRCA 1 have been reported as a high risk factor in the family who inherited and have been related to familial ovarian cancer (Tavani et al., 2000).
Consequence of BRCA mutations
If there is subsequent inactivation of BRCA allele in the opposite chromosome, the development of cancer in BRCA germline mutation carriers occurs. Later, the elimination of remaining normal copy of the BRCA gene may be detected as loss of heterozygosity. It is considered to be a necessary and early step in the cancer pathway in germline BRCA malignancies (Boyd et al., 2000; Levine et al., 2001). This inactivation may occur through genetic recombination or genetic mutations. Gene inactivation may also occur through epigenetic changes, the individual develop by successive differentiation of an unstructured egg. The loss of DNA repair function subsequent to the loss of all BRCA function permits the accumulation of unrepaired somatic mutation, which is a requirement to the development of ovarian cancer.