Department of Molecular Genetics, Erasmus MC, University Erasmus Medical Center Rotterdam, 3000 CA, The Netherlands.
Oncode Institute, Erasmus MC, University Erasmus Medical Center Rotterdam, 3000 CA, The Netherlands.
Nucleic Acids Res. 2018 Oct 12;46(18):9563-9577. doi: 10.1093/nar/gky774.
The structure-specific ERCC1-XPF endonuclease plays a key role in DNA damage excision by nucleotide excision repair (NER) and interstrand crosslink repair. Mutations in this complex can either cause xeroderma pigmentosum (XP) or XP combined with Cockayne syndrome (XPCS-complex) or Fanconi anemia. However, most patients carry compound heterozygous mutations, which confounds the dissection of the phenotypic consequences for each of the identified XPF alleles. Here, we analyzed the functional impact of individual pathogenic XPF alleles on NER. We show that XP-causing mutations diminish XPF recruitment to DNA damage and only mildly affect global genome NER. In contrast, an XPCS-complex-specific mutation causes persistent recruitment of XPF and the upstream core NER machinery to DNA damage and severely impairs both global genome and transcription-coupled NER. Remarkably, persistence of NER factors at DNA damage appears to be a common feature of XPCS-complex cells, suggesting that this could be a determining factor contributing to the development of additional developmental and/or neurodegenerative features in XP patients.
结构特异性 ERCC1-XPF 内切酶在核苷酸切除修复 (NER) 和链间交联修复中发挥关键作用，切除 DNA 损伤。该复合物中的突变要么导致着色性干皮病 (XP) ，要么导致 XP 与 Cockayne 综合征 (XPCS-复合物) 或范可尼贫血症的组合。然而，大多数患者携带复合杂合突变，这使得对每个鉴定的 XPF 等位基因的表型后果进行剖析变得复杂。在这里，我们分析了个体致病 XPF 等位基因对 NER 的功能影响。我们表明，导致 XP 的突变会减少 XPF 对 DNA 损伤的募集，并且仅轻度影响全基因组 NER。相比之下，XPCS-复合物特异性突变导致 XPF 和上游核心 NER 机制持续募集到 DNA 损伤处，并严重损害全基因组和转录偶联 NER。值得注意的是，NER 因子在 DNA 损伤处的持续存在似乎是 XPCS-复合物细胞的一个共同特征，这表明这可能是导致 XP 患者出现额外发育和/或神经退行性特征的一个决定性因素。
