BRCA1通过异染色质介导的沉默抑制肿瘤

Abstract

 抑癌基因BRCA1的变异导致乳腺和/或卵巢癌症。 这里我们显示缺失Brca1的小鼠去抑制串联重复卫星DNA转录。 Brca1 缺失伴随了基因组内致密DNA区域的减少和卫星重复序列组蛋白H2A泛素化的丢失。BRCA1在体内结合到卫星DNA区域并泛素化H2A。异位表达的H2A融合到泛素抵消了BRCA1丢失的效应，表明BRCA1通过泛素化组蛋白H2A保持了异染色质结构。卫星DNA去抑制现象也可以在老鼠和人类BRCA1缺失的乳腺癌中观察到。异位表达卫星DNA能够表型模拟BRCA1丢失后导致的中心体扩增，细胞周期检验点缺陷，DNA损坏和基因组不稳定。我们认为BRCA1在保持全异染色质完整的角色在其肿瘤抑制功能方面起作用。

原文摘要

BRCA1 tumour suppression occurs via heterochromatin-mediated silencing.

Zhu Q, Pao GM, Huynh AM, Suh H, Tonnu N, Nederlof PM, Gage FH, Verma IM.

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

Abstract

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.

Nature. 2011 Sep 7;477(7363):179-84. doi: 10.1038/nature10371.

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