Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair.
Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair.
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DOI：
10.1016/j.molcel.2014.03.014
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发表时间：
2014-05-08
期刊：
影响因子：
16
通讯作者：
Patel, Ketan J.
中科院分区：
文献类型：
--
作者：
Hodskinson, Michael R. G.;Silhan, Jan;Crossan, Gerry P.;Garaycoechea, Juan I.;Mukherjee, Shivam;Johnson, Christopher M.;Schaerer, Orlando D.;Patel, Ketan J.
SLX 4与三种核酸酶（XPF-ERCC 1、MUS 81-EME 1和SLX 1）结合，其缺陷导致基因组不稳定、对DNA交联剂敏感和范可尼贫血。然而，SLX 4及其相关核酸酶如何在DNA交联修复中起作用尚不清楚。在这里，我们揭示了小鼠Slx 4缺陷的后果，并揭示了其在DNA交联修复中的功能。Slx 4缺陷小鼠发生上皮癌并具有收缩的造血干细胞库。SLX 4的N-末端结构域（mini-SLX 4）仅与XPF-ERCC 1结合，足以赋予对DNA交联剂的抗性。重组mini-SLX 4增强XPF-ERCC 1核酸酶活性高达100倍，指导对DNA叉的特异性。Mini-SLX 4-XPF-ERCC 1还可以强烈刺激嵌入合成复制叉中的DNA交联周围的双切口，这是修复这种损伤的重要步骤。这些观察结果将脊椎动物SLX 4定义为肿瘤抑制因子，其在DNA交联修复中激活XPF-ERCC 1核酸酶特异性。SLX 4抑制肿瘤发生并有助于维持小鼠中的HSPC池SLX 4将XPF-ERCC 1的核酸酶活性增强高达100倍。在复合物中，SLX 4-XPF-ERCC 1有效地解开DNA交联SLX 4与多种核酸酶相互作用，可以促进DNA链间交联（ICL）的修复。Hodskinson等人评估Slx 4缺陷在小鼠中的长期后果，并表明SLX 4和XPF-ERCC 1核酸酶之间的相互作用可以支持ICL修复。生化分析表明，SLX 4刺激XPF-ERCC 1核酸酶切割复制中间体并解开ICL。
SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repair. SLX4 suppresses tumorigenesis and contributes to the maintenance of HSPC pool in mice SLX4 enhances the nuclease activity of XPF-ERCC1 up to 100-fold In complex, SLX4-XPF-ERCC1 efficiently unhooks a DNA crosslink SLX4 interacts with multiple nucleases that can facilitate the repair of DNA interstrand crosslinks (ICLs). Hodskinson et al. assess the long-term consequences of Slx4 deficiency in mice and show that the interaction between SLX4 and XPF-ERCC1 nuclease can support ICL repair. Biochemical analysis reveals that SLX4 stimulates XPF-ERCC1 nuclease to cut replication intermediates and unhook an ICL.
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