Mutations in the tumour-suppressor gene BRCA1 predispose individuals to breast and ovarian cancer. The protein has been assigned many functions though, so how does its deficiency contribute to tumorigenesis? Ronit Yarden et al. report in Nature Genetics that BRCA1 is involved in cell-cycle arrest following DNA damage, which allows cells time to repair their DNA.

The breast cancer cell line HCC1937 possesses just one copy of BRCA1, and this contains an inactivating mutation that is associated with an increased cancer risk. These cells are unable to arrest following γ-irradiation, but transfection with BRCA1 restores this ability.

As cells arrest at the G2/M checkpoint by inhibiting the CDC2–cyclin-B kinase, Yarden et al. determined the protein levels and activity of CDC2–cyclin-B in HCC1937 cells and those transfected with BRCA1. Both expression of cyclin B1 and activity of the CDC2–cyclin-B kinase are decreased in BRCA1-expressing cells.

CDC2–cyclin-B activity is negatively regulated by the phosphorylation of CDC2's Tyr15 residue, so are the proteins that control Tyr15 phosphorylation also regulated by BRCA1? CDC25C, the activatory phosphatase, is downregulated after irradiation in BRCA1-expressing cells, and this corresponds with an increase in the inhibitory kinase WEE1 and the level of phosphorylated CDC2-Tyr15. 14-3-3 proteins, which transport CDC25C from the nucleus following DNA damage to prevent activation of CDC2–cyclin-B, are also upregulated in BRCA1-expressing cells, and immunofluorescence revealed that CDC25C is, indeed, cytoplasmic in BRCA1-expressing cells.

But how does BRCA1 induce these effects? CHK1 and CHK2 are essential for the cell-cycle arrest in response to DNA damage, so might BRCA1 activate one of these checkpoint proteins? BRCA1 physically interacts with CHK1 and stimulates its activity after DNA damage. The G2/M arrest is also dependent on CHK1, as BRCA1-expressing cells that were treated with a CHK1 inhibitor lost the ability to induce this arrest.

BRCA1 therefore seems to be the link between the DNA-damage-sensing proteins ATM and ATR — which phosphorylate BRCA1 — and downstream members of the G2/M checkpoint pathway. So BRCA1 maintains genome stability by allowing cells time to repair their DNA following DNA damage. Only time will tell if it also inhibits tumorigenesis by other mechanisms.