Mutations in ERCC4, Encoding the DNA-Repair Endonuclease XPF, Cause Fanconi Anemia
Mutations in ERCC4, Encoding the DNA-Repair Endonuclease XPF, Cause Fanconi Anemia
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DOI：
10.1016/j.ajhg.2013.04.002
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发表时间：
2013-05-02
影响因子：
9.8
通讯作者：
Surralles, Jordi
中科院分区：
文献类型：
--
作者：
Bogliolo, Massimo;Schuster, Beatrice;Surralles, Jordi
范可尼贫血（FA）是一种罕见的基因组不稳定疾病，其特征是进行性骨髓衰竭和易患癌症。 FA 相关基因产物参与 DNA 链间交联 (ICL) 的修复。已鉴定出 15 个 FA 相关基因，但某些个体的遗传基础仍未解决。在这里，我们对未分类的 FA 个体的 DNA 使用全外显子组和桑格测序，发现了 ERCC4 (XPF) 中的双等位基因种系突变，ERCC4 (XPF) 是一种结构特异性核酸酶编码基因，之前与着色性干皮病和节段性 XFE 早衰综合征有关。遗传逆转和野生型 ERCC4 cDNA 补充了 FA 细胞系的表型，提供了 ERCC4 突变导致这种 FA 亚型的遗传证据。进一步的生化和功能分析表明，已确定的 FA 引起的 ERCC4 突变强烈破坏 DNA ICL 修复中 XPF 的功能，而不会严重损害核苷酸切除修复。我们的数据显示，根据 ERCC4 突变的类型以及由此产生的两种 DNA 修复活性之间的平衡，个体会出现三种临床上不同的疾病之一，这凸显了 XPF 核酸内切酶在基因组稳定性和人类疾病中的多功能性质。
Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.