The Bloom's syndrome helicase suppresses crossing over during homologous recombination
The Bloom's syndrome helicase suppresses crossing over during homologous recombination
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DOI：
10.1038/nature02253
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发表时间：
2003-12-18
期刊：
影响因子：
64.8
通讯作者：
Hickson, ID
中科院分区：
文献类型：
--
作者：
Wu, L;Hickson, ID
编码 RecQ 解旋酶的 BLM 突变会导致布卢姆综合征，这是一种与癌症易感性和基因组不稳定相关的疾病 (1)。布卢姆综合征的一个显着特征是姐妹染色单体交换频率升高(2)。这些是由同源重组过程中染色单体臂的交叉引起的，同源重组是修复 DNA 双链断裂和受损复制叉的普遍过程。虽然减数分裂需要交换，但在有丝分裂细胞中，它可能与杂合性的有害损失有关。 BLM 与人类拓扑异构酶 IIIalpha (hTOPO IIIalpha)(3,4) 形成进化上保守的复合物，该复合物可以断裂并重新连接 DNA 以改变其拓扑结构。任一蛋白质同源物的失活都会导致单细胞生物中的过度重组(5)。在这里，我们证明 BLM 和 hTOPO IIIalpha 共同影响含有双霍利迪连接体的重组中间体的分辨率。这种机制，我们称之为双连接点溶解，与经典的霍利迪连接点溶解不同，可以防止侧翼序列的交换。这种活性的丧失可以解释布卢姆综合征的许多细胞表型。这些结果对于我们理解同源重组过程和预防肿瘤发生的机制具有更广泛的意义。
Mutations in BLM, which encodes a RecQ helicase, give rise to Bloom's syndrome, a disorder associated with cancer predisposition and genomic instability(1). A defining feature of Bloom's syndrome is an elevated frequency of sister chromatid exchanges(2). These arise from crossing over of chromatid arms during homologous recombination, a ubiquitous process that exists to repair DNA double-stranded breaks and damaged replication forks. Whereas crossing over is required in meiosis, in mitotic cells it can be associated with detrimental loss of heterozygosity. BLM forms an evolutionarily conserved complex with human topoisomerase IIIalpha (hTOPO IIIalpha)(3,4), which can break and rejoin DNA to alter its topology. Inactivation of homologues of either protein leads to hyper-recombination in unicellular organisms(5). Here, we show that BLM and hTOPO IIIalpha together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which we term double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom's syndrome. These results have wider implications for our understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.