The human BRCA1 gene encodes a 1863-amino acid protein, which contains a highly conserved RING finger domain at the amino terminus and two BRCT repeats at the carboxyl terminus (Fig. 1). The vast majority of cancer-predisposing mutations of BRCA1 give rise to truncated and presumably nonfunctional proteins (3). Approximately 10% of mutations result in change of a single amino acid, many of which are located in the RING and BRCT domains. The molecular functions of the BRCA1 protein have been a subject of intense research for more than a decade. The ubiquitously expressed protein is implicated in a large array of cellular events, including DNA repair, transcription, chromatin remodeling, ubiquitination, DNA damage checkpoint, mitotic spindle checkpoint, and control of centrosome duplication (7, 13-21).
Among all the reported functions of BRCA1, its role in the DNA damage response has been most extensively investigated (13, 14, 16, 18). A wealth of evidence indicates that BRCA1 is physically associated with multiple proteins involved in DNA repair and checkpoint control, and their nuclear co-localization is one of the hallmarks in the activation of DNA damage response (22-26). BRCA1 is phosphorylated by several key protein kinases involved in the DNA damage checkpoint control, including ATM, ATR, and CHK2 (27-29), and is thought to act as a signal-transducing molecule that links upstream sensors of DNA damage with the downstream effectors. BRCA1 -deficient human and murine cells are hypersensitive to various types of genotoxic insults, including DNA double-strand breaks (30-34). Chromosomal instability due to compromised functions of BRCA1 in DNA repair and DNA damage checkpoint most likely contribute in a significant manner to BRCA1 mutation-associated cancer susceptibility.
In addition to DNA repair, the role of BRCA1 in gene regulation has also been well explored (7, 13, 15, 21). Although BRCA1 is not a sequence-specific DNA binding protein, it can be associated with a number of site-specific transcription factors (35-41), chromatin-modifying protein complexes (42-45), and the RNA polymerase II (RNAPII) holo-enzyme itself (42, 46-48). Ectopic expression and siRNA knockdown experiments have led to the identification of a number of BRCA1 target genes including p21CIP, GADD45, pS2/TFF1, MAD2, OPN, and ANG1 (35, 39, 40, 49-56). Many of the BRCA1-regulated genes are important players in cell cycle regulation, mitotic checkpoint, cell migration, and angiogenesis, and their aberrant expression due to the loss of BRCA1 activity in transcription may lead to the BRCA1 mutation-associated tumorigenesis.
So far the only known enzymatic activity of BRCA1 is its ubiquitin (Ub) E3 ligase activity. The N-terminal RING domain of BRCA1 interacts with another structurally similar RING finger protein BARD1, and the BRCA1/BARD1 heterodimer confers strong Ub E3 ligase activity in vitro (19, 57). Importantly, missense cancer-predisposing mutations in the RING domain of BRCA1 abolish the Ub E3 ligase activity of the BRCA1/BARD1 complex, providing a compelling link between ubiquity-nation and breast cancer. The exact in vivo ubiquitination substrates of the BRCA1/BARD1 complex remain to be elucidated. However, recent studies have indicated that ubiquitination of the largest subunit of RNA polymerase II by BRCA1/BARD1 is responsible for DNA damage-induced inhibition of RNA processing (58, 59). In addition, BRCA1/BARD1 has been shown to ubiquitinate y-tubulin, which is involved in the control of proper centrosome duplication and chromosomal segregation (60).
The construction of whole-body and tissue-specific BRCA1 knockout mice has allowed for a better understanding of the role that Brca1 plays in both embryonic development and tumorigenesis in vivo. Whole-body BRCA1 knockout mice fail to develop properly and die in utero before day 7.5 of gestation (61). Characterization of the embryonic lethal pheno-type in the BRCA1 null embryos suggested that they exhibited defects in cellular proliferation (61). Further studies with this knockout mouse model indicated that loss of functional p53 delayed embryonic lethality in BRCA1 null mice to day 9.5 of gestation, suggesting that BRCA1 and p53 participate in a common genetic pathway (62). Relatively recent work by Cao et al. demonstrated how the interplay between BRCA1 and p53 affected both cell growth and metastatic potential in MEFs isolated from the knockout mice (63). In this system, loss of BRCA1 results in p53-dependent senescence, therefore allowing clonal selection for cells that can bypass senescence through loss of functional p53. Interestingly, the immortalization of BRCA1-null MEFs was observed to occur with a much lower frequency than BRCA1++ controls and nearly every immortalized clone was shown to be p5 3-negative. Once immortalized, the BRCA1 null MEFs proliferated at a significantly greater rate and exhibited greater metastatic potential than immortalized control MEFs. The results from these studies begin to reconcile the seeming paradox between the accepted function of BRCA1 as a tumor suppressor and the slow growth phenotype of BRCA1 mutant/null cells in culture. Consistent with the findings from the laboratory research, studies of human clinical samples indicate that BRCA1 mutation-associated breast cancers exhibit inactivating mutations in the p53 gene with a greater frequency than their sporadic counterparts (64).
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