Nucleolytic processing of aberrant replication intermediates by an Exo1-Dna2-Sae2 axis counteracts fork collapse-driven chromosome instability.
Nucleolytic processing of aberrant replication intermediates by an Exo1-Dna2-Sae2 axis counteracts fork collapse-driven chromosome instability.
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DOI：
10.1093/nar/gkw858
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发表时间：
2016-12-15
影响因子：
14.9
通讯作者：
Bermejo R
中科院分区：
文献类型：
--
作者：
Colosio A;Frattini C;Pellicanò G;Villa-Hernández S;Bermejo R
DNA复制过程中的问题是基因组不稳定和驱动恶性转化的基础。DNA损伤检查点稳定停滞的复制叉，从而抵消异常叉过渡，DNA断裂和染色体重排。我们通过将补骨脂素交联与复制中间体二维凝胶分析相结合，分析了检查点缺陷细胞中的叉加工。这揭示了Exo1核酸酶在切除反向复制叉结构和抵消类似叉切割产物的异常中间体积累方面的新作用。遗传分析表明，Exo1与Mus81、Dna2和Sae2核酸酶在促进复制应激后的细胞存活方面具有功能上的相互作用，这提示了停滞分叉的协同核分解过程。虽然Mus81和其他结构特异性内切酶不会导致明显的分叉断裂转变，但Dna2可能通过促进Exo1进入新生链来促进叉的反向切除。相反，Sae2与Exo1合作，抵消了与双链断裂形成和增加的总染色体重排率相关的假定叉裂事件。我们的数据表明，在检查点缺陷细胞中，多种核酸酶活性相互作用，消除异常复制中间体，防止染色体不稳定。
Problems during DNA replication underlie genomic instability and drive malignant transformation. The DNA damage checkpoint stabilizes stalled replication forks thus counteracting aberrant fork transitions, DNA breaks and chromosomal rearrangements. We analyzed fork processing in checkpoint deficient cells by coupling psoralen crosslinking with replication intermediate two-dimensional gel analysis. This revealed a novel role for Exo1 nuclease in resecting reversed replication fork structures and counteracting the accumulation of aberrant intermediates resembling fork cleavage products. Genetic analyses demonstrated a functional interplay of Exo1 with Mus81, Dna2 and Sae2 nucleases in promoting cell survival following replication stress, suggestive of concerted nucleolytic processing of stalled forks. While Mus81 and other Structure Specific Endonucleases do not contribute to obvious collapsed fork transitions, Dna2 promotes reversed fork resection likely by facilitating Exo1 access to nascent strands. Instead, Sae2 cooperates with Exo1 in counteracting putative fork cleavage events linked to double strand breaks formation and increased gross chromosomal rearrangement rates. Our data indicate that in checkpoint deficient cells diverse nuclease activities interface to eliminate aberrant replication intermediates and prevent chromosome instability.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
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64.8
作者：
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通讯作者：
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影响因子：
10.5
作者：
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通讯作者：
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