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BRCA1 tumour suppression occurs via heterochromatin- mediated silencing

机译：BRCA1肿瘤抑制通过异染色质介导的沉默发生

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摘要

Mutations in the tumour suppressor gene BRCA1 lead to breast and/ or ovarian cancer. Here we show that loss of Brcal in mice results in transcriptional de-repression of the tandemly repeated satellite DNA. Brcal 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 BRCAl-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.
机译：肿瘤抑制基因BRCA1中的突变会导致乳腺癌和/或卵巢癌。在这里，我们显示，小鼠中Brcal的丢失导致串联重复的卫星DNA的转录去抑制。黄铜缺乏症伴随着基因组中缩合DNA区域的减少以及组蛋白H2A在卫星重复序列中泛素化的丧失。 BRCA1与卫星DNA区域结合并在体内泛素化H2A。 H2A与泛素融合的异位表达逆转了BRCA1丢失的影响，表明BRCA1通过组蛋白H2A的泛素化保持了异染色质结构。在小鼠和人类缺乏BRCA1的乳腺癌中也观察到卫星DNA的抑制。卫星DNA的异位表达可在中心体扩增，细胞周期检查点缺陷，DNA损伤和基因组不稳定中表型BRCA1丢失。我们建议BRCA1在维持整体异染色质完整性中的作用解释了其许多抑癌功能。

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  • 来源
    《Nature》 |2011年第7363期|p.179-184|共6页
  • 作者

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

  • 作者单位

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Department of Pathology, the Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.;

    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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