BRCA1 tumour suppression occurs via heterochromatin-mediated silencing

Mutations in the tumour suppressor gene BRCA1 lead to breast and/or ovarian cancer. Herewe show that loss of Brca1 in mice results in transcriptional de-repression of the tandemly repeated satellite DNA.Brca1deficiency is accompanied by a reduction of condensedDNA regions in the genome and loss of ubiquitylation of histoneH2A at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNAde-repressionwas also observed inmouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNAcanphenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNAdamage and genomic instability. We propose that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions.