Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
Genes Cells. 2012 Mar;17(3):173-85. doi: 10.1111/j.1365-2443.2012.01582.x.
The xeroderma pigmentosum group F-cross-complementing rodent repair deficiency group 1 (XPF-ERCC1) complex is a structure-specific endonuclease involved in nucleotide excision repair (NER) and interstrand cross-link (ICL) repair. Patients with XPF mutations may suffer from two forms of xeroderma pigmentosum (XP): XP-F patients show mild photosensitivity and proneness to skin cancer but rarely show any neurological abnormalities, whereas XFE patients display symptoms of severe XP symptoms, growth retardation and accelerated aging. Xpf knockout mice display accelerated aging and die before weaning. These results suggest that the XPF-ERCC1 complex has additional functions besides NER and ICL repair and is essential for development and growth. In this study, we show a partial colocalization of XPF with mitotic spindles and Eg5. XPF knockdown in cells led to an increase in the frequency of abnormal nuclear morphology and mitosis. Similarly, the frequency of abnormal nuclei and mitosis was increased in XP-F and XFE cells. In addition, we showed that Eg5 enhances the action of XPF-ERCC1 nuclease activity. Taken together, these results suggest that the interaction between XPF and Eg5 plays a role in mitosis and DNA repair and offer new insights into the pathogenesis of XP-F and XFE.
着色性干皮病组 F 交叉互补修复缺陷组 1（XPF-ERCC1）复合物是一种结构特异性内切酶，参与核苷酸切除修复（NER）和链间交联（ICL）修复。XPF 突变的患者可能患有两种形式的着色性干皮病（XP）：XP-F 患者表现出轻微的光敏感性和皮肤癌易感性，但很少表现出任何神经异常，而 XFE 患者则表现出严重 XP 症状、生长迟缓加速老化。Xpf 敲除小鼠表现出加速老化，在断奶前死亡。这些结果表明，XPF-ERCC1 复合物除了 NER 和 ICL 修复之外还有其他功能，对发育和生长至关重要。在这项研究中，我们显示 XPF 与有丝分裂纺锤体和 Eg5 有部分共定位。细胞中的 XPF 敲低导致异常核形态和有丝分裂的频率增加。同样，在 XP-F 和 XFE 细胞中，异常核和有丝分裂的频率也增加。此外，我们表明 Eg5 增强了 XPF-ERCC1 核酸酶活性的作用。总之，这些结果表明 XPF 和 Eg5 之间的相互作用在有丝分裂和 DNA 修复中发挥作用，并为 XP-F 和 XFE 的发病机制提供了新的见解。
