Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Nature. 2011 Sep 7;477(7363):179-84. 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.
抑癌基因 BRCA1 的突变会导致乳腺癌和/或卵巢癌。在这里，我们发现小鼠中 Brca1 的缺失会导致串联重复卫星 DNA 的转录去阻遏。Brca1 缺陷伴随着基因组中凝聚 DNA 区域的减少和卫星重复处组蛋白 H2A 的泛素化丧失。BRCA1 结合到卫星 DNA 区域，并在体内泛素化 H2A。与泛素融合的 H2A 的异位表达逆转了 BRCA1 缺失的影响，表明 BRCA1 通过组蛋白 H2A 的泛素化来维持异染色质结构。在小鼠和人 BRCA1 缺陷型乳腺癌中也观察到了卫星 DNA 的去阻遏。卫星 DNA 的异位表达可以模拟 BRCA1 缺失在中心体扩增、细胞周期检查点缺陷、DNA 损伤和基因组不稳定性方面的作用。我们提出，BRCA1 维持全局异染色质完整性的作用解释了其许多肿瘤抑制功能。
