Replication stress induces sister-chromatid bridging at fragile site loci in mitosis
Replication stress induces sister-chromatid bridging at fragile site loci in mitosis
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DOI：
10.1038/ncb1882
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发表时间：
2009-06-01
影响因子：
21.3
通讯作者：
Hickson, Ian D.
中科院分区：
文献类型：
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作者：
Chan, Kok Lung;Palmai-Pallag, Timea;Hickson, Ian D.
人类的几种遗传综合征与癌症易感性有关。在其中两种疾病中，BLM（布卢姆综合征中的解旋酶缺陷）（1）和FANCA-N（范可尼贫血中的缺陷）（2）的基因产物缺陷，在称为BRAFT的多酶复合物中缔合（3）。这些蛋白质如何抑制肿瘤发生仍不清楚，尽管这两种情况都与染色体不稳定性有关。在这里，我们表明，范可尼贫血蛋白FANCD 2和FANCI特别与常见的脆性位点位点，无论是否染色体断裂。出乎意料的是，这些基因座经常通过BLM相关的超细DNA桥（4）（UFB）相互连接，即使细胞穿过有丝分裂。与脆性位点表达类似（5），在DNA复制部分抑制后诱导脆性位点桥接。我们建议，复制应力后，姐妹染色单体是相互联系的复制中间体主要在遗传基因座与内在的复制困难，如脆弱的网站。在Bloom综合征细胞中，脆性位点DNA键的无效解析引起后期UFB和含有脆性位点DNA的微核数量增加。我们的数据具有普遍意义的贡献脆性位点基因座染色体不稳定性和肿瘤发生。
Several inherited syndromes in humans are associated with cancer predisposition. The gene products defective in two of these disorders, BLM ( a helicase defective in Bloom's syndrome)(1) and FANC A-N ( defective in Fanconi anaemia)(2), associate in a multienzyme complex called BRAFT(3). How these proteins suppress tumorigenesis remains unclear, although both conditions are associated with chromosome instability. Here we show that the Fanconi anaemia proteins FANCD2 and FANCI specifically associate with common fragile site loci irrespective of whether the chromosome is broken. Unexpectedly, these loci are frequently interlinked through BLM-associated ultra-fine DNA bridges(4) (UFBs) even as cells traverse mitosis. Similarly to fragile site expression(5), fragile site bridging is induced after partial inhibition of DNA replication. We propose that, after replication stress, sister chromatids are interlinked by replication intermediates primarily at genetic loci with intrinsic replication difficulties, such as fragile sites. In Bloom's syndrome cells, inefficient resolution of DNA linkages at fragile sites gives rise to increased numbers of anaphase UFBs and micronuclei containing fragile site DNA. Our data have general implications concerning the contribution of fragile site loci to chromosomal instability and tumorigenesis.