Ctf4 Prevents Genome Rearrangements by Suppressing DNA Double-Strand Break Formation and Its End Resection at Arrested Replication Forks
Ctf4 Prevents Genome Rearrangements by Suppressing DNA Double-Strand Break Formation and Its End Resection at Arrested Replication Forks
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DOI：
10.1016/j.molcel.2017.04.020
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发表时间：
2017-05-18
期刊：
影响因子：
16
通讯作者：
Kobayashi, Takehiko
中科院分区：
文献类型：
--
作者：
Sasaki, Mariko;Kobayashi, Takehiko
复制叉的停滞导致DNA双链断裂（DSB），这是基因组重排的主要来源。然而，在断叉的背景下，DSB修复仍然知之甚少。在这里，我们表明，DSB在芽殖酵母核糖体RNA基因（rDNA）位点的被捕叉形成通常修复的途径依赖于Mre 11-Rad 50-Xrs 2复合物，但独立的HR。HR也是DSB修复停滞叉tRNA基因。相比之下，在缺乏核心复制体组分Ctf 4的细胞中，DSB更频繁地形成，并且这些DSB经历末端切除和HR介导的修复，其倾向于rDNA超扩增;这突出了Ctf 4作为DSB末端切除的关键调节剂在被捕叉处。末端切除也发生在生理rDNA扩增过程中，即使在Ctf 4的存在下。因此，末端切除的抑制对于保护在被阻止的叉处的DSB免于染色体重排是重要的。
Arrested replication forks lead to DNA double-strand breaks (DSBs), which are a major source of genome rearrangements. Yet DSB repair in the context of broken forks remains poorly understood. Here we demonstrate that DSBs that are formed at arrested forks in the budding yeast ribosomal RNA gene (rDNA) locus are normally repaired by pathways dependent on the Mre11-Rad50-Xrs2 complex but independent of HR. HR is also dispensable for DSB repair at stalled forks at tRNA genes. In contrast, in cells lacking the core replisome component Ctf4, DSBs are formed more frequently, and these DSBs undergo end resection and HR-mediated repair that is prone to rDNA hyper-amplification; this highlights Ctf4 as a key regulator of DSB end resection at arrested forks. End resection also occurs during physiological rDNA amplification even in the presence of Ctf4. Suppression of end resection is thus important for protecting DSBs at arrested forks from chromosome rearrangements.