Role of BRCA1 in DNA Damage Response

To deal with many types of damage, genomes have evolved multiple cellular defense mechanisms, including DNA repair and cell cycle checkpoint processes. BRCA1 is a tumor suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. BRCA1-associated genome surveillance complex (BASC) is a complex containing BRCA1 that is key to recognizing and repairing DNA damage. This complex includes tumor suppressors and DNA damage repair proteins MSH2, MSH6, MLH1, ATM, BLM, and the Rad50-MRE11-NBS1 protein complex. In addition, RFC, a protein complex that facilitates the loading of PCNA onto DNA, is also part of BASC.Eleven or more genetically distinct groups of Fanconi's Anemia (FA) have been described (FANCA, B, C, D1, D2, G, E, F and CL), each caused by recessive mutations in a different gene. DNA damage activates the monoubiquitylation of FANCD2, which is targeted to subnuclear foci, where it co-localizes with BRCA1 and Rad51. BRCA1 further interacts with Rad51 and with the Rad50-MRE11-NBS1 complex. BRCA1 exists mostly as a heterodimeric complex with BARD1, a protein that is involved in BRCA1-mediated tumor suppression. The ring finger of BRCA1 contains ubiquitin ligase activity that is markedly enhanced when complexed with BARD1, and is required for the function of this tumor suppressor protein in protecting genomic integrity. BRCA1-BARD1 complexes co-localize with DNA replication and repair factors in response to DNA damage. The ATM and ATR kinases, both implicated in responses to genotoxic stress, are involved in radiation-induced phosphorylation of BRCA1. Normally, ATM phosphorylates Chk2, which in turn phosphorylates BRCA1. ATR and ATM kinase targets also include repair enzymes like Rad51, Chk1 and Chk2. In response to ionizing radiation, ATM phosphorylates NBS1 leading to phosphorylation of FANCD2 and the establishment of an S-Phase checkpoint response, and in response to mitomycin C or hydroxyurea, NBS1 assembles in nuclear foci with MRE11-Rad50 and FANCD2. Like ATM, the MRE11 complex is a crucial upstream regulator of checkpoint responses and DNA-repair responses in all eukaryotic cells. The MRE11 complex assembles with BRCA1 in nuclear foci following DNA damage and regulates homologous recombination repair. BRCA2 functions upstream in the pathway by promoting FA complex assembly and FANCD2 activation, or downstream by transducing signals from FA proteins to Rad51.BRCA1 activation of the GADD45 promoter is mediated through the OCT1 and CAAT motifs located at the GADD45 promoter region. BRCA1 can trigger a G1 arrest that is mediated by transcriptional activation of p21Waf1/Cip1. In addition to its association with holoenzyme, BRCA1 can bind to several different transcription factors, including p53, Myc, STAT1, and CtIP. BRCA1 acts in concert with STAT1 to differentially activate transcription of a subset of IFN-γ target genes and mediates growth inhibition by this cytokine. BRCA1 binds preferentially to the hypo-phosphorylated form of Rb protein. The carboxy-terminal region of BRCA1 is a functionally significant domain. CtIP interacts specifically with the carboxy-terminal segment of BRCA1, but the exact function of CtIP is unknown. The BRCA1 RING finger associates with ATF1 and leads to transcriptional activation of ATF1 target genes, some of which are involved in the transcriptional response to DNA damage. DNA repair by homologous recombination is mediated by the BRCA1-associated surveillance complex (BLM, MSH2-MSH6 and MRE11-Rad50-NBS1). BRCA1 form complexes with both BACH1 and SWI/SNF to mediate chromatin remodeling and homologous recombination. HDACs regulate the access of the SWI/SNF-BRCA1 complex to DNA. Finally, BRCA1 interacts with Chk1 and PLK1 to regulate the G2/M and G1/S checkpoints, possibly via GADD45, thereby linking BRCA1 to the regulation of apoptosis.