BRCA1 tumor suppressor network: focusing on its tail

Abstract

Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine). The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3][4][5][6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,[7][8][9][10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9][10][11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming...

Rap80 Protein Recruitment to DNA Double-strand Breaks Requires Binding to Both Small Ubiquitin-like Modifier (SUMO) and Ubiquitin Conjugates

“…Through its C-terminal BRCT domains, BRCA1 forms at least three different complexes, the BRCA1-A, BRCA1-B, and BRCA1-C complexes, by binding to Abraxas (Abra1), Bach1, and CtIP, respectively (5,7,8). Although all three complexes have been indicated in the role of BRCA1 in cell cycle checkpoint control and DNA repair, the BRCA1-A complex is known to target BRCA1 to DNA damage sites in response to DNA damageinduced Ub modification.…”

“…Although all three complexes have been indicated in the role of BRCA1 in cell cycle checkpoint control and DNA repair, the BRCA1-A complex is known to target BRCA1 to DNA damage sites in response to DNA damageinduced Ub modification. The BRCA1-A complex contains at least five different components: Abraxas, NBA1/MERIT40, BRE, Rap80, and BRCC36 (8). Rap80 contains two ubiquitininteracting motif (UIM) domains that display a binding specificity toward Ub Lys-63 linkage chains generated through RNF8/RNF168 E3 ligases at sites of damage.…”

The role of epigenetic transcriptional regulation in BRCA1-mediated tumor suppression

“…Our current understanding of BRCA1's function is based largely on the role of its interacting proteins. 3,4 The RING domain has been shown to interact with 6 A number of substrates have been shown to be ubiquitinated by the BRCA1-BARD1 heterodimer. 7 For example, it was recently reported that BRCA1 monoubiquitinates histone H2A at satellite repeats and suppresses the expression of major and minor satellite transcripts.…”

Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

“…BRCA1-B is composed of BRCA1, TopBP1, and BACH1, and is involved in DNA replication stress-induced checkpoint and DNA interstrand crosslink (ICL) repair [36]. BACH1 interacts with BRCT domain of BRCA1 through phosphoserine (p-S990) and its phosphorylation occurs in a cell-cycle-dependent manner, with the strongest interaction between BRCA1 and BACH1 during S-phase [14,37].…”