Abstract
BRCA1 is a large multi-domain protein with a pivotal role in maintaining genome stability and cell cycle progression. Germline mutations in the BRCA1 gene confer an estimated lifetime risk of 60%–80% for breast cancer and 15%–60% for ovarian cancer. Many of the germline mutations associated with cancer development are concentrated in the amino terminal RING domain and the carboxyl terminal BRCT motifs of BRCA1, which are the most well-characterized regions of the protein. The function of BRCA1 in DNA repair, transcription and cell cycle control through the DNA damage response is orchestrated through its association with an impressive repertoire of protein complexes. The association of BRCA1 with ATM/ATR, CHK2 and Aurora A protein kinases regulates cell cycle progression, whilst its association with RAD51 has a direct impact on the repair of double strand DNA breaks (DSBs) by homologous recombination (HR). BRCA1 interactions with the MRN complex of proteins, with the BRCC complex of proteins that exhibit E3 ligase activity and with the phosphor proteins CtIP, BACH1 (BRIP1) and Abraxas (CCDC98) are also implicated in DNA repair mechanisms and cell cycle checkpoint control. BRCA1 through its association with specific proteins and multi-protein complexes is a sentinel of the normal cell cycle control and DNA repair.
Highlights
BRCA1 is a well known tumor suppressor gene identified in the nineties and germline mutations in this gene confer increased susceptibility to developing breast and ovarian cancer [1,2]
Between the nuclear localization signals and the C-terminus of BRCA1 is a region that is not known to exhibit homology to any other proteins, but this domain is implicated in the interaction of BRCA1 with a number of proteins that function in the DNA repair process and the cell cycle checkpoint control
Mutation in the RING domain of BRCA1 that does not disrupt its heterodimerization with BARD1, but abolishes its E3 ligase activity firstly does not cause embryonic lethality and animals grow to normal adulthood, male animals are sterile; and secondly the rate of spontaneous tumor formation is the same as in animals expressing wild type BRCA1 suggesting that it is not the E3 ligase activity of BRCA1 that confers its tumor suppression function [69]
Summary
BRCA1 is a well known tumor suppressor gene identified in the nineties and germline mutations in this gene confer increased susceptibility to developing breast and ovarian cancer [1,2]. Between the nuclear localization signals and the C-terminus of BRCA1 is a region that is not known to exhibit homology to any other proteins, but this domain is implicated in the interaction of BRCA1 with a number of proteins that function in the DNA repair process and the cell cycle checkpoint control. The BRCT domains of BRCA1 mediate the interaction with signaling kinases and other proteins involved in cell cycle checkpoints Both the RING and BRCT domains of BRCA1 are of utmost importance for normal BRCA1 function and it is not surprising that a large number of breast cancer predisposing mutations are located in both of these two domains (See Breast Cancer Information Core Data base [18]). We will review some of the best characterized interactions of BRCA1 and their functional implications
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