nature20130110-9

揭示DNA复制叉在染色体重排中的作用,加深了我们对染色体重排机制的了解。

-2013年1月10日版《自然》

中文翻译


【译文】DNA复制叉在染色体重排机制中的作用

【译文】DNA复制障碍能诱发染色体重排(GCRs)以及拷贝数变异(CNVs)。GCRs和CNVs是人类基因组疾病的基础,同时也是癌症的特征。癌症发展过程中,环境因素与驱动致癌基因的增殖促进了复制压力。GCRs和CNVs促进了癌症发展,同时也给癌症治疗带来阻力。当压力阻止DNA复制时,DNA复制子和停顿的DNA复制叉处于连接状态,且受到S期监测点的保护。当所受压力得到缓解时,停顿的DNA复制叉可重新进行有效复制。然而,当DNA聚合酶从DNA复制叉(简称解离DNA复制叉)解离时或者复制叉结构被破坏时,DNA复制则需要同源重组或者是microhomology介导,才能重新启动。本研究确定了是裂殖酵母中同源重组体启动了DNA复制叉。我们确认了染色体重排的新机制,通过观察发现DNA复制叉重启动具有执行短重复反向序列中U-turn的倾向。由此,我们提出重新启动DNA复制叉容易出错的特点,能诱发癌症中的GCRs和基因扩增以及基因组疾病中

英文原稿


[Title]: Recombination-restarted replication makes inverted chromosome fusions at inverted repeats

[Authors]:Ken’Ichi Mizuno,1 Izumi Miyabe,1 Stephanie A. Schalbetter,1 Antony M. Carr1 & Johanne M. Murray1

[Abstract]Impediments to DNA replication are known to induce gross chromosomal rearrangements (GCRs) and copy-number variations (CNVs). GCRs and CNVs underlie human genomic disorders and are a feature of cancer. During cancer development, environmental factors and oncogene-driven proliferation promote replication stress. Resulting GCRs and CNVs are proposed to contribute to cancer development and therapy resistance. When stress arrests replication, the replisome remains associated with the fork DNA (stalled fork) and is protected by the inter-S-phase checkpoint. Stalled forks efficiently resume when the stress is relieved. However, if the polymerases dissociate from the fork (fork collapse) or the fork structure breaks (broken fork), replication restart can proceed either by homologous recombination or microhomology-primed re-initiation. Here we ascertain the consequences of replication with a fork restarted by homologous recombination in fission yeast. We identify a new mechanism of chromosomal rearrangement through the observation that recombination-restarted forks have a considerably high propensity to execute a U-turn at small inverted repeats (up to 1 in 40 replication events). We propose that the error-prone nature of restarted forks contributes to the generation of GCRs and gene amplification in cancer, and to non-recurrent CNVs in genomic disorders.

原文地址

http://www.nature.com/nature/journal/v493/n7431/full/nature11676.html

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