693, BRCA1 branches out from its DNA repair duties. Images from Pageau and Lawrence suggest that this tumor suppressor also helps out during heterochromatin replication.
Repair is the function usually ascribed to BRCA1, which accumulates at damaged DNA in irradiated cells. But undamaged cells also have nuclear BRCA1 foci. They appear mostly during S phase, but because the foci do not have a clear-cut overlap with the majority of replicating DNA, their function has been difficult to explain.
The new results reveal an association of nuclear BRCA1 foci specifically with subsets of replicating heterochromatin. In mouse cells, highly heterochromatic centromeres gather in easily stained clusters known as chromocenters. In cells that are replicating these bright blocks, the BRCA1 association was readily apparent. The authors also noted the same association in human cells.
This isn't the first time BRCA1 has been linked with heterochromatin. A previous report suggested an association of BRCA1 with the Xist RNA along the inactive X chromosome. But the 3D images in this issue show that BRCA1 is only adjacent to Xist territories and that it also abuts the constitutive heterochromatin of autosomal chromosomes.
The authors hope now to better characterize the timing of BRCA1's arrival relative to replication. If BRCA1 arrives before DNA polymerase, it might help to open up tightly wound heterochromatin, perhaps by interacting with chromatin-remodeling factors. But if it arrives later, BRCA1 might be helping to reassemble and unkink replicated chromatin, possibly through its reported ability to activate topoisomerase II.
Breast cancer cells that lacked BRCA1 were more prone to mitotic defects, including lagging DNA bridges containing centromeric sequences between daughter cells. BRCA1 might thus be needed for the maintenance of centromere-linked heterochromatin. Mitotic problems and the potential for widespread expression of normally silent heterochromatin are efficient ways in which BRCA1 mutant cells could acquire cancerous traits even beyond any failures in DNA repair.