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BRCA1 tumour suppression occurs via heterochromatin-mediated silencing

2011; Nature Portfolio; Volume: 477; Issue: 7363 Linguagem: Inglês

10.1038/nature10371

1476-4687

Quan Zhu, Gerald M. Pao, Alexis Huynh, Hoonkyo Suh, Nina Tonnu, Petra M. Nederlof, Fred H. Gage, Inder M. Verma,

Genetic factors in colorectal cancer

Mutations in the tumour suppressor gene BRCA1 lead to breast and/or ovarian cancer. Here we show that loss of Brca1 in mice results in transcriptional de-repression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A 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 DNA de-repression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage and genomic instability. We propose that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions. The BRCA1 protein is a tumour suppressor associated with hereditary breast and ovarian cancer. Inder Verma and colleagues now describe a previously unknown function for BRCA1 that could be relevant to cancer causation. BRCA1 deficiency in mice is shown to impair the integrity of constitutive heterochromatin and to disrupt gene silencing at satellite repeat regions through the loss of ubiquitylation of histone H2A. Abnormal transcription of satellite repeats also occurs in human breast cancer samples deficient in BRCA1, a possible cause of genomic instability and thereby tumorigenesis.