Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template
Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template
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DOI：
10.1101/gad.226373.113
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发表时间：
2013-12-01
影响因子：
10.5
通讯作者：
Lopes, Massimo
中科院分区：
文献类型：
--
作者：
Neelsen, Kai J.;Zanini, Isabella M. Y.;Lopes, Massimo
放松管制的原产地许可和重组促进了基因组的不稳定性和肿瘤的发生，其机制在很大程度上难以捉摸。研究早期有丝分裂抑制剂1 （Emi1）在人类细胞中耗散的后果，我们通过DNA纤维标记表明，起源再激活发生迅速，远早于bbb4n DNA的细胞积累，并与检查点盲ssDNA间隙和复制叉逆转有关。一旦细胞完成大量DNA复制，大量RPA染色质装载、小染色体片段的形成和检查点激活就会在稍后发生。我们提出，不受管制的起始触发导致新复制的DNA上未被检测到的不连续性，最终导致复制分叉的断裂。
Deregulated origin licensing and rereplication promote genome instability and tumorigenesis by largely elusive mechanisms. Investigating the consequences of Early mitotic inhibitor 1 ( Emi1) depletion in human cells, previously associated with rereplication, we show by DNA fiber labeling that origin reactivation occurs rapidly, well before accumulation of cells with >4N DNA, and is associated with checkpoint- blind ssDNA gaps and replication fork reversal. Massive RPA chromatin loading, formation of small chromosomal fragments, and checkpoint activation occur only later, once cells complete bulk DNA replication. We propose that deregulated origin firing leads to undetected discontinuities on newly replicated DNA, which ultimately cause breakage of rereplicating forks.