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首页> 美国卫生研究院文献>other >The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity causing aneuploidy-associated cancers
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The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity causing aneuploidy-associated cancers

机译：FEN1 E359K种系突变破坏FEN1-WRN相互作用和FEN1 GEN活性导致与非整倍性相关的癌症

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摘要

Polymorphisms and somatic mutations in Flap Endonuclease 1 (FEN1), an essential enzyme involved in DNA replication and repair, can lead to functional deficiencies of the FEN1 protein and a predisposition to cancer. We identified a FEN1 germline mutation which changed residue E359 to K in a patient whose family had a history of breast cancer. We determined that the E359K mutation, which is in the protein-protein domain of FEN1, abolished the interaction of FEN1 with Werner Syndrome protein (WRN), an interaction which is critical for resolving stalled DNA replication forks. Furthermore, although the flap endonuclease activity of FEN1 E359K was unaffected, it failed to resolve bubble structures, which requires the FEN1 gap dependent endonuclease (GEN) activity. To determine the etiological significance of E359K, we established a mouse model containing this mutation. E359K mouse embryonic fibroblasts (MEF) were more sensitive to DNA cross-linking agents that cause replication forks to stall. Cytological analysis suggested that the FEN1-WRN interaction was also required to for telomere stability; mutant cell lines had fragile telomeres, increased numbers of spontaneous chromosomal anomalies and higher frequencies of transformation. Moreover, the incidence of cancer was significantly higher in mice homozygous for FEN1 E359K than in wild-type mice, suggesting that the FEN1 E359K mutation is oncogenic.
机译：皮瓣内切核酸酶1（FEN1）（一种参与DNA复制和修复的必需酶）的多态性和体细胞突变可导致FEN1蛋白的功能缺陷和易患癌症。我们鉴定了一个FEN1种系突变，该突变将一名家族有乳腺癌病史的患者的E359残基改变为K。我们确定在FEN1的蛋白质-蛋白质结构域中的E359K突变消除了FEN1与Werner综合征蛋白质（WRN）的相互作用，该相互作用对于解决停滞的DNA复制叉至关重要。此外，尽管FEN1 E359K的皮瓣内切核酸酶活性未受影响，但未能解析气泡结构，这需要FEN1缺口依赖性核酸内切酶（GEN）活性。为了确定E359K的病因学意义，我们建立了包含此突变的小鼠模型。 E359K小鼠胚胎成纤维细胞（MEF）对导致复制叉停滞的DNA交联剂更敏感。细胞学分析表明，端粒稳定性也需要FEN1-WRN相互作用。突变细胞系具有脆弱的端粒，自发染色体异常数量增加和转化频率更高。此外，FEN1 E359K纯合子小鼠的癌症发生率显着高于野生型小鼠，表明FEN1 E359K突变是致癌的。

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