BRCA1 and Its Network of Interacting Partners

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.

Expression and mutations of BRCA in breast cancer and ovarian cancer: Evidence from bioinformatics analyses

“…It is now clear that the BRcA1 and BRcA2 proteins co-localize with RAd51 complexes on mitotic and meiotic chromosomes following exposure to ionizing radiation or hydroxyurea (7,29). certain other proteins have been reported to interact with BRcA1, including ataxia telangiectasia mutated (ATM)/ATM-related kinase, checkpoint kinase 2, and aurora A protein kinase, to regulate cell cycle progression (30). In the present study, three genes (NF1, SYCP2 and TP53) were found to be associated with BRCA1 in breast cancer and ovarian cancer.…”

Wwox–Brca1 interaction: role in DNA repair pathway choice

“…Therefore, we propose that in Wwox-sufficient cells, Wwox binds Brca1, directly or indirectly, along this central region, competing with other Brca1-interacting proteins critical for promoting HDR. One candidate, Rad50, a component of the MRN complex, binds Brca1 at aa 341–758 32 . This interaction is responsible for stimulating nuclease activity of CtIP and MRN to enable end-resection, which commits cells to HDR or SSA.…”

Homologous DNA Repair:Safeguarding Genome Territories from Knives

“…Following signal transmission in S/G2 phase, ctlp dissociates from BRCA1 and associates with MRN complex where it exclusively facilitates DNA end-resection and retention of MRN complex at DNA damage site [26][27][28][29][30] . However, BRCA1 (N-terminal, 341-748 amino acids) directly associates with MRN complex via RAD50 component.…”

“…However, BRCA1 (N-terminal, 341-748 amino acids) directly associates with MRN complex via RAD50 component. Earlier, it was only reported that BRCA1-MRN complex remain intact throughout HDR repair and very soon it was found that this process is partly dependent on ATM/ATR mediated hyper-phosphorylation of BRCA1 and CHK2 activation 26,28 . To initiate HDR repair, damaged double strand DNA ends are resected by MRN complex to expose ssDNA ends 5,22 .…”

“…Importantly, in S-phase synchronized cells, BRCA1 does not simultaneously interact with MRN and BRCC complexes at the damaged DNA sites. Conversely, mutually exclusive BRCA1-MRN heterodimer, as sensor of DNA damage, signals to recruit downstream machinery of damage repair including the BRCC complex 33 at DNA damage sites whilst BRCC directly functions in HDR repair pathway 15,28,34 . In fact, it is still unclear what is exactly the BRCC complex needed for in HR, however it was found that its E3 ligase activity stimulates this BRCC complex to mobilize and stabilize at resected DNA sites.…”