DNA Damage Response Mediated through BRCA1

Abstract

The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast and ovarian cancer syndromes in women. The tumor suppressor, BRCA1 is known as a major player in the DNA damage response. These are evident from its loss, which causes malignant transformation in breast and ovary, and renders cells to become sensitive to a wide variety of DNA damaging agents. Here, we have implications on functional coupling of the pleiotropic roles of BRCA1, including DNA damage signal networking, DNA repair, transcription, and checkpoint of cell cycle, to tumor suppression by examining the molecular mechanisms and functions of BRCA1. The breast cancer susceptibility 1 (BRCA1) gene was identified and mapped to chromosome 17q21 by analyzing families at high risk from breast and ovarian cancer, and was first cloned in 1994 (1). The BRCA1 gene encodes a large nuclear protein that is ubiquitously expressed in a number of tissues. BRCA1 shares little structural resemblance to the majority of other known proteins (Fig. 1). Its ortholog is only found in mammals but not in yeast, fly, worm, or zebra fish, indicating that BRCA1 may come later in evolution and it may have more specialized and tissue-specific functions in mammalian cells. Although a number of studies delineating and deciphering the real biological roles of BRCA1 have accumulated, understanding these BRCA1 unique features still remains to be challengingly elucidated. Fig. 1 A schematic diagram of the BRCA1 polypeptide and its interaction with different proteins. BRCA1 polypeptide has the phosphorylation sites (Ⓟ) shown as the seine residues that are phosphorylated and the kinases responsible. The proteins that are ... BRCA1 as a tumor suppressor The BRCA1 mutations account for about 80% of families whose members have a high incidence of both breast and ovarian cancers (2). The BRCA1 gene fits the profile of a classical 'tumor suppressor gene,' since the breast and ovarian cancers that develop in carriers of BRCA1 gene mutations almost always exhibit loss of the wild-type BRCA1 allele (1). The BRCA1 protein consists of 1863 amino acids (Fig. 1) and is expressed in most proliferating cells (1). The C-terminus of BRCA1 contains an amino-acid sequence motif, now known as a BRCT domain (Fig. 1), recognized in many DNA repair proteins. The BRCT domain of BRCA1 mediates protein interactions that are critical to its role in transcriptional regulation, signaling networking, and the response to DNA damage. The germline mutations in the BRCA1 mutation carriers are frequently found in the BRCT domain, suggesting that the BRCT domain is important for its diverse biological roles. In the N-terminus, there is a ring-finger domain (Fig. 1), also allowing for protein-protein interactions, and thought to be involved in protein ubiquitination. Disruption of the ring domain (by the mutations C61G or C64G) blocked the ability of BRCA1 to repress estrogen receptor-α (ER-α) signaling and to modulate DNA repair, chemosensitivity, and apoptosis. These findings suggest that the ring domain mediates critical protein interactions, and disruption of which contributes to carcinogenesis. Additionally, a variety of structural domains in BRCA1 with these distinct functions hint at diverse roles of BRCA1 in multiple cellular processes. Recent epidemiologic studies indicate that BRCA1 mutation carriers have a high lifetime risk of breast cancer of up to 80%. In addition to the breast cancer risk, women with BRCA1 mutations have an increased risk of ovarian cancer. These works solidify the concept that BRCA1 functions as a tumor suppressor. Despite the multiple lines of strong evidences supporting the function of BRCA1 as a tumor suppressor, the mechanisms and the precise roles through which BRCA1 loss leads to tumorigenesis remain to be determined.