DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage.
DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage.
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DOI：
10.1126/science.aaa8391
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发表时间：
2015-08-14
期刊：
影响因子：
--
通讯作者：
Ira G
中科院分区：
文献类型：
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作者：
Mayle R;Campbell IM;Beck CR;Yu Y;Wilson M;Shaw CA;Bjergbaek L;Lupski JR;Ira G
大多数自发 DNA 双链断裂 (DSB) 是由复制叉断裂引起的。断裂诱导复制 (BIR) 是一种基因组易重排修复机制，需要真核 DNA Polδ 的 Pol32/POLD3 亚基，被提出用于修复断裂的分叉，但如何避免基因组不稳定尚不清楚。我们表明，断裂的叉修复最初使用容易出错的 Pol32 依赖性合成，但诱变合成仅限于 Mus81 核酸内切酶和会聚叉断裂后的几千个碱基范围内。 Mus81 抑制同源序列和不同的人类 Alu 重复元件之间的模板转换，突出了其对于高度重复基因组稳定性的重要性。我们认为，缺乏及时聚合叉或 Mus81 可能会加剧癌症中观察到的基因组不稳定。
Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.