Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Hum Mutat. 2013 Mar;34(3):481-9. doi: 10.1002/humu.22259. Epub 2013 Jan 17.
Nucleotide excision repair (NER) is the most flexible of all known DNA-repair mechanisms, and XPG is a 3'-endonuclease that participates in NER. Mutations in this gene (ERCC5) may result in the human syndrome xeroderma pigmentosum (XP) and, in some cases, in the complex phenotype of Cockayne syndrome (CS). Two Brazilian XP siblings, who were mildly affected, were investigated and classified into the XP-G group. The cells from these patients were highly ultraviolet (UV) sensitive but not sensitive to photosensitized methylene blue, an agent that causes oxidative stress. This phenotype is in contrast to XP-G/CS cells, which are highly sensitive to this oxidative agent. Sequencing revealed a compound heterozygous genotype with two novel missense mutations: c.83C>A (p.Ala28Asp) and c.2904G>C (p.Trp968Cys). The first mutation maps to the catalytic site of the XPG protein, whereas the second may compromise binding to DNA. Functional assays indicated that the mutated alleles were unable to perform the complete repair of UV-irradiated plasmids; however, full correction was observed for oxidatively damaged plasmids. Therefore, the XP phenotype of these patients is caused by novel missense mutations that specifically affect DNA repair for UV- but not oxidative-stress-induced DNA damage, and implications for XP versus XP/CS phenotype are discussed.
核苷酸切除修复（NER）是所有已知的 DNA 修复机制中最灵活的，而 XPG 是参与 NER 的 3'-核酸内切酶。该基因（ERCC5）的突变可能导致人类着色性干皮病（XP），在某些情况下，还可能导致 Cockayne 综合征（CS）的复杂表型。两名患有轻度 XP 的巴西 XP 兄弟姐妹接受了调查，并被归类为 XP-G 组。这些患者的细胞对紫外线（UV）高度敏感，但对光敏亚甲蓝不敏感，亚甲蓝是一种引起氧化应激的试剂。这种表型与 XP-G/CS 细胞形成对比，后者对这种氧化剂高度敏感。测序显示存在复合杂合基因型，有两个新的错义突变：c.83C>A（p.Ala28Asp）和 c.2904G>C（p.Trp968Cys）。第一个突变映射到 XPG 蛋白的催化位点，而第二个突变可能影响与 DNA 的结合。功能测定表明，突变等位基因无法完全修复 UV 照射的质粒；然而，氧化损伤的质粒完全得到了校正。因此，这些患者的 XP 表型是由新的错义突变引起的，这些突变专门影响针对 UV 而非氧化应激诱导的 DNA 损伤的 DNA 修复，并且讨论了 XP 与 XP/CS 表型的相关性。
