The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair.
The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair.
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DOI：
10.1371/journal.pgen.1001025
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发表时间：
2010-07-15
期刊：
影响因子：
4.5
通讯作者：
Gartner A
中科院分区：
文献类型：
--
作者：
Bailly AP;Freeman A;Hall J;Déclais AC;Alpi A;Lilley DM;Ahmed S;Gartner A
DNA 双链断裂 (DSB) 可以通过同源重组 (HR) 进行修复，其中可能涉及霍利迪连接体 (HJ) 中间体，最终由溶核酶解决。人类 GEN1 的 N 末端片段最近被证明可充当霍利迪连接体解离酶，但人们对 GEN-1 在体内的作用知之甚少。霍利迪连接体解析标志着 DNA 修复的完成，这一步骤可能与信号蛋白结合，调节细胞周期进程以响应 DNA 损伤。使用正向遗传学方法，我们鉴定了与人类 GEN1 霍利迪连接体解析酶同源的秀丽隐杆线虫双功能 DNA 双链断裂修复和 DNA 损伤信号蛋白。 GEN-1具有与人类酶相关的生化活性，促进DNA双链断裂的修复，但对于减数分裂重组期间DNA双链断裂的修复不是必需的。突变分析表明，GEN-1 的 DNA 损伤信号传导功能与其在 DNA 修复中的作用是分开的。 GEN-1 通过与 RPA 加载、CHK1 激活和 CEP-1/p53 介导的细胞凋亡诱导介导的经典 DNA 损伤反应途径平行发挥作用的途径促进生殖细胞周期停滞和细胞凋亡。此外，GEN-1 与 9-1-1 复合体冗余地发挥作用，以确保基因组稳定性。我们的研究表明，GEN-1 可能充当双功能霍利迪连接体解析酶，可协调 DNA 损伤信号传导与 DNA 双链断裂修复的后期步骤。 DNA 修复与细胞周期进程和细胞凋亡的协调是 DNA 损伤反应机制的核心任务。重组修复和减数分裂重组的关键中间体于 1964 年首次提出，涉及四链 DNA 结构。这些中间产物必须在 DNA 修复完成后得到解决，以实现正确的染色体分离。利用正向遗传学，我们鉴定出与人类 GEN1 霍利迪连接体解析酶同源的秀丽隐杆线虫双功能 DNA 双链断裂修复和 DNA 损伤信号蛋白。 GEN-1促进DNA双链断裂的修复，但对于减数分裂重组过程中DNA双链断裂的修复不是必需的。 GEN-1 的 DNA 损伤信号传导功能与其在 DNA 修复中的作用是分开的。出乎意料的是，GEN-1 定义了一条 DNA 损伤信号传导途径，其作用与 CHK-1 磷酸化和 CEP-1/p53 介导的经典途径平行。因此，能够解析霍利迪连接的酶可能会直接将 DNA 修复的后期步骤与响应 DNA 损伤而调节细胞周期进程的途径偶联。
DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53–mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair. Coordination of DNA repair with cell cycle progression and apoptosis is a central task of the DNA damage response machinery. A key intermediate of recombinational repair and meiotic recombination, first proposed in 1964, involves four-stranded DNA structures. These intermediates have to be resolved upon completion of DNA repair to allow for proper chromosome segregation. Using forward genetics, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. The DNA damage signaling function of GEN-1 is separable from its role in DNA repair. Unexpectedly, GEN-1 defines a DNA damage-signaling pathway that acts in parallel to the canonical pathway mediated by CHK-1 phosphorylation and CEP-1/p53. Thus, an enzyme that can resolve Holliday junctions may directly couple a late step in DNA repair to a pathway that regulates cell cycle progression in response to DNA damage.
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