BRCA1 tumour suppression occurs via heterochromatin-mediated silencing

Abstract

Mutations in tumor suppressor BRCA1 lead to breast and/or ovarian cancer. Here we show that loss of BRCA1 in mice results in transcriptional derepression of the tandemly repeated satellite DNA. BRCA1 deficiency is accompanied by reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A at satellite repeats. BRCA1 binds to satellite DNA regions in vivo and ubiquitylates H2A in vitro. Ectopic expression of an H2A fused to ubiquitin reverses the effects of BRCA1 loss, suggesting that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA derepression was also observed 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 tumor suppressor functions.

Pericentric and centromeric transcription: a perfect balance required

“…When BRCA1 is knocked out, there is a global increase in both major and minor satellite transcription in mouse cells, and of alpha satellite in human cells, concomitant with a loss of H2A ubiquitination (Fig. 2b); other effects included a reduction in heterochromatin centers as well as numerous mitotic defects and an increase in DNA doublestrand breaks (Zhu et al 2011). In contrast to the work of Ting et al (2011), there was no observable increase in LINE or other retrotransposable element activity associated with PCT and CT increases (Zhu et al 2011).…”

“…2b); other effects included a reduction in heterochromatin centers as well as numerous mitotic defects and an increase in DNA doublestrand breaks (Zhu et al 2011). In contrast to the work of Ting et al (2011), there was no observable increase in LINE or other retrotransposable element activity associated with PCT and CT increases (Zhu et al 2011). Thus, while the loss of H2A ubiquitination, via loss of BRCA1 function, may be responsible for converting heterochromatin into an open chromatin state and allowing transcription, it remains unknown what factors or sequences promote the observed satellite transcription in BRCA1-deficient cells.…”

“…A few recent studies have addressed how and why centromeric transcription changes during oncogenesis (Frescas et al 2008;Iotti et al 2011;Slee et al 2012;Ting et al 2011;Zhu et al 2011). The tumor suppressor lysine-specific demethylase 2A (KDM2A) was identified as a heterochromatin associated protein that is downregulated in prostate cancer (Frescas et al 2008).…”

“…Since BRCA1 mutation leads to genomic instability, it has been predicted to function in DNA replication, DNA damage repair, cell cycle control, and a host of other mitotic and regulatory functions. Recently, BRCA1 was discovered to be involved in maintaining specific epigenetic states within centromeric and pericentric regions (Zhu et al 2011). BRCA1 protein, through an E3 ligase activity in its RING finger domain, is responsible for monoubiquitinating the histone H2A (Chen et al 2002).…”

“…Interestingly, transcripts emanating from both the pericentromere and centromere core have been identified in a multitude of organisms (Eymery et al 2009a;Stimpson and Sullivan 2010). Moreover, recent studies have identified proteins that interact with these transcripts (Topp et al 2004;Wong et al 2007;Chueh et al 2009;Ferri et al 2009;Du et al 2010;Hsieh et al 2011), analyzed the effects of increased and decreased transcription on genome stability (Bergmann et al 2011;Ohkuni and Kitagawa 2011;Bergmann et al 2012), or identified changes in transcription in stressed or diseased cells (Eymery et al 2009b;Gopalakrishnan et al 2009;Ting et al 2011;Zhu et al 2011). In this review, we will present pericentric and centromeric noncoding RNA transcription and discuss its diverse roles in modified histone recruitment, centromere function and stability, and insulator activity as well as newly discovered correlations between centromere and pericentromere transcription and human disease.…”