BRCA1 tumour suppression occurs via heterochromatin-mediated silencing

• Published in: Nature (London) Vol. 477; no. 7363; pp. 179 - 184
• Main Authors: Zhu, Quan, Pao, Gerald M., Huynh, Alexis M., Suh, Hoonkyo, Tonnu, Nina, Nederlof, Petra M., Gage, Fred H., Verma, Inder M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.09.2011; Nature Publishing Group
• Subjects: 631/337/100/101; 631/67/581; 631/67/68; Animals; Biological and medical sciences; BRCA1 Protein - deficiency; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Breast - cytology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Line, Tumor; Cells, Cultured; Chromatin; DNA, Satellite - genetics; Epigenetics; Epithelial Cells - metabolism; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, BRCA1 - physiology; Genetic aspects; Genetics; Genomic Instability - genetics; Gynecology. Andrology. Obstetrics; HeLa Cells; Heterochromatin - genetics; Heterochromatin - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Mammary gland diseases; Medical sciences; Mice; multidisciplinary; Ovarian cancer; Ovarian Neoplasms - genetics; Physiological aspects; Proteins; RNA, Messenger - genetics; Science; Science (multidisciplinary); Transcription, Genetic - genetics; Tumor suppressor genes; Tumors; Ubiquitin-Protein Ligases - metabolism; Ubiquitinated Proteins - metabolism; Ubiquitination; United States; Netherlands; Human; Breast disease; Rodentia; Breast cancer; Malignant tumor; Mammary gland diseases; Vertebrata; Heterochromatin; Mammalia; Cancerology; Mouse; Animal; Genetics; BRCA1 gene; Cancer; Tumor suppressor gene
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10371

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. BRCA1 mutation linked to genomic instability 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.