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首页> 外文期刊>Molecular and Cellular Biology >Functional Interplay of the Mre11 Nuclease and Ku in the Response to Replication-Associated DNA Damage
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Functional Interplay of the Mre11 Nuclease and Ku in the Response to Replication-Associated DNA Damage

机译：Mre11核酸酶和Ku在复制相关的DNA损伤响应中的功能相互作用。

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The Mre11 complex is a central component of the DNA damage response, with roles in damage sensing, molecular bridging, and end resection. We have previously shown that in Saccharomyces cerevisiae, Ku70 (yKu70) deficiency reduces the ionizing radiation sensitivity of mre11Δ mutants. In this study, we show that yKu70 deficiency suppressed the camptothecin (CPT) and methyl methanesulfonate (MMS) sensitivity of nuclease-deficient mre11-3 and sae2Δ mutants in an Exo1-dependent manner. CPT-induced G2/M arrest, γ-H2AX persistence, and chromosome breaks were elevated in mre11-3 mutants. These outcomes were reduced by yKu70 deficiency. Given that the genotoxic effects of CPT are manifest during DNA replication, these data suggest that Ku limits Exo1-dependent double-strand break (DSB) resection during DNA replication, inhibiting the initial processing steps required for homology-directed repair. We propose that Mre11 nuclease- and Sae2-dependent DNA end processing, which initiates DSB resection prevents Ku from engaging DSBs, thus promoting Exo1-dependent resection. In agreement with this idea, we show that Ku affinity for binding to short single-stranded overhangs is much lower than for blunt DNA ends. Collectively, the data define a nonhomologous end joining (NHEJ)-independent, S-phase-specific function of the Ku heterodimer.
机译：Mre11复合物是DNA损伤反应的重要组成部分，在损伤感测，分子桥联和末端切除中发挥作用。先前我们已经表明，在酿酒酵母中，Ku70（yKu70）缺乏会降低 mre11 Δ突变体的电离辐射敏感性。在这项研究中，我们表明yKu70缺乏抑制了核酸酶缺陷的 mre11 - 3 和sae2Δ的喜树碱（CPT）和甲磺酸甲酯（MMS）的敏感性。 em>依赖于Exo1的突变体。在 mre11 - 3 突变体中，CPT诱导的G 2 / M阻滞，γ-H2AX持久性和染色体断裂增加。 yKu70缺乏症降低了这些结局。鉴于CPT的遗传毒性作用在DNA复制过程中很明显，因此这些数据表明Ku限制了DNA复制过程中Exo1依赖的双链断裂（DSB）切除，从而抑制了同源指导修复所需的初始加工步骤。我们建议启动DSB切除的Mre11核酸酶和Sae2依赖的DNA末端加工阻止Ku参与DSB，从而促进Exo1依赖的切除。与这个想法相一致，我们表明Ku亲和力与短单链突出端的结合远低于钝的DNA末端。总体而言，数据定义了Ku异二聚体的非同源末端连接（NHEJ）独立，S相特异性功能。

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