Patterns of chromosomal fragmentation due to uracil-DNA incorporation reveal a novel mechanism of replication-dependent double-stranded breaks
Patterns of chromosomal fragmentation due to uracil-DNA incorporation reveal a novel mechanism of replication-dependent double-stranded breaks
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DOI：
10.1111/j.1365-2958.2008.06149.x
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Kuzminov, Andrei
中科院分区：
文献类型：
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作者：
Kouzminova, Elena A.;Kuzminov, Andrei
越来越多的证据表明，自发染色体断裂（遗传不稳定性的主要原因之一）与DNA复制密切相关。特别是，我们之前提出，DNA中尿嘧啶的掺入会因尿嘧啶切除中间体处的复制叉崩溃而引发染色体断裂。我们通过确定DNA复制与特定染色体区段的断裂模式之间的关系，在大肠杆菌的dut突变体中在染色体水平上对该模型的预测进行了测试。在此我们表明，尿嘧啶 - DNA引发的染色体断裂：（i）具有与复制梯度平行的梯度，（ii）在指向复制起点的特定区段内显示极性，以及（iii）重新组织以匹配诱导的复制梯度，证实了其动态模式。出乎意料的是，这些断裂模式不仅支持复制叉崩溃模型，而且还揭示了由尿嘧啶切除引发的依赖复制的染色体断裂的另一种机制。
There is growing evidence that spontaneous chromosomal fragmentation, one of the main contributors to genetic instability, is intimately linked to DNA replication. In particular, we proposed before that uracil incorporation in DNA triggers chromosomal fragmentation due to replication fork collapse at uracil-excision intermediates. We tested predictions of this model at the chromosomal level in the dut mutants of Escherichia coli, by determining the relationship between DNA replication and patterns of fragmentation in defined chromosomal segments. Here we show that the uracil-DNA-triggered chromosomal fragmentation: (i) has a gradient that parallels the replication gradient, (ii) shows polarity within defined segments pointing towards replication origins and (iii) reorganizes to match induced replication gradients, confirming its dynamic pattern. Unexpectedly, these fragmentation patterns not only support the replication fork collapse model, but also reveal another mechanism of the replication-dependent chromosomal fragmentation triggered by uracil excision.