The breast and ovarian cancer susceptibility gene, BRCA1, has been cloned and shown to encode a zinc-finger protein of unknown function. BRCA1, as BRCA2, contributes to homologous recombination and DNA repair, to embryonic proliferation, to transcriptional regulation and, for BRCA1, to ubiquitination. BRCA1 is a tumour suppressor that has important roles in the protection against genomic instability.

Function > homologous recombination and DNA repair

BRCA1 plays essential roles in homologous recombinational repair, non-homologous end joining, and nucleotide excision repair. BRCA1 mediates these functions by interaction with components of the DNA repair machinery and by regulating expression of genes that are involved in these DNA damage repair pathways.

Function > ubiquitination

BRCA1 associates with BARD1 to form a RING/RING heterodimer. The BRCA1/BARD1 RING complex functions as an ubiquitin (Ub) ligase with activity substantially greater than individual BRCA1 or BARD1 subunits.

The BRCA1 tumor suppressor forms a heterodimer with the BARD1 protein, and the resulting complex functions as an E3 ubiquitin ligase that catalyzes the synthesis of polyubiquitin chains.

UbcH5c and UbcH7 also interact with the BRCA1/BARD1 complex with similar affinity. Although the in vivo substrate(s) is not yet known, BRCA1 has been observed to undergo autoubiquitination and is capable of monoubiquitinating histones 2A and 2AX in vitro.

BASC

BRCA1 is the protein defective in some cases of hereditary breast cancer susceptibility. The recent identification of RECQL3 as part of the BRCA1-associated genome surveillance complex (BASC), links RECQL3 with a number of tumour suppressor and DNA damage repair proteins.

The BASC complex includes MSH2, MHS6, MLH1, ATM, RECQL3, the RAD50-MRE11-NBS1 complex and DNA replication factor C. Many components of this complex have roles in recognition of DNA damage/unusual DNA structures, suggestive of this complex performing some kind of 'sensor' role.

To examine the role of RECQL3 within BASC, the subcellular localization of RECQL3 and BRCA1 was analysed before and after exposure to DNA damaging agents. In untreated cells, RECQL3 and BRCA1 colocalization was limited to a few bright nuclear foci.

However, after treatment with hydroxyurea or ionizing radiation, colocalization was greatly enhanced in those cells that were in mid-to-late S phase or in G2.

This could be indicative of specific requirement for BLM/BRCA1 in replication/repair of late replicating DNA.

Consistent with a role for BLM (possibly within BASC) in recognizing abnormal DNA structures, it has been shown that RECQL3 is able to unwind a variety of unusual DNA structures, including G-quadruplex, synthetic X-junctions (models for the Holliday junction), bubbles and forked DNA.

Pathology

 The absence of BRCA1 results in accumulation of chromosome damage, cell cycle abnormalities and apoptosis, leading to developmental abnormalities and adult tumorigenesis.

 Germline mutations in BRCA1 confer high risks of breast and ovarian cancer.

 Mutations in BRCA1 account for at least 80% of families with both breast and ovarian cancer, as well as some non-familial sporadic ovarian cancers. The loss of wild-type BRCA1 in tumours of individuals carrying one nonfunctional BRCA1 allele suggests that BRCA1 encodes a tumour suppressor that may inhibit the proliferation of mammary epithelial cells.

 Cells lacking BRCA1 are hypersensitive to many DNA-damaging agents such as ultraviolet light and ionizing radiation, and show defects in both S- and G2/M-checkpoint activation following exposure to ionizing radiation.

 BRCA1 is a target for both ataxia telangiectasia mutated (ATM)- and ataxia telangiectasia and Rad3 related (ATR)-mediated phosphorylation.

 BRCA1 can interact with numerous proteins through its many protein-protein interaction domains. Interestingly, BRCA1 interacts under normal conditions with the elongating form of RNA polymerase II, but following genotoxic insult BRCA1 becomes phosphorylated and dissociates from the transcription complex.

 So, BRCA1 and associated DNA-damage surveillance factors might be associated with the elongating form of RNA polymerase II and might monitor the elongation success of the RNA polymerase.

 When transcription halts at a lesion or is disrupted in some other way, BRCA1 and associated factors might relocate to recruit DNA-repair enzymes and to activate cell-cycle checkpoints.

Animal models

 BRCA1-/- knock-out mice (#8563759#)

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