Preventing Nonhomologous End Joining Suppresses DNA Repair Defects of Fanconi Anemia
Preventing Nonhomologous End Joining Suppresses DNA Repair Defects of Fanconi Anemia
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DOI：
10.1016/j.molcel.2010.06.026
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发表时间：
2010-07-09
期刊：
影响因子：
16
通讯作者：
La Volpe, Adriana
中科院分区：
文献类型：
--
作者：
Adamo, Adele;Collis, Spencer J.;La Volpe, Adriana
范可尼贫血（Fanconi anemia， FA）是一种复杂的癌症易感性疾病，与DNA修复缺陷和不孕症有关，但FA蛋白在基因组维持中的确切功能尚不清楚。本研究报告秀丽隐杆线虫FANCD2 （fcd-2）在正常减数分裂重组中是不需要的，但在交叉缺陷突变体中需要FANCD2 （fcd-2）来防止非同源末端连接（NHEJ）对减数分裂断裂的非法修复。在有丝分裂细胞中，我们发现消除NHEJ可以显著抑制秀丽隐杆线虫fcd-2突变体和fa缺陷的人类细胞的DNA修复缺陷。此外，在缺乏FANCD2的情况下，NHEJ因子被不恰当地招募到复制应激位点。我们的研究结果与DNA修复过程中NHEJ混杂作用导致FA的解释一致。我们认为FA通路的一个关键功能是引导病变进入准确的修复通路，而不是容易出错的修复通路。
Fanconi anemia (FA) is a complex cancer susceptibility disorder associated with DNA repair defects and infertility, yet the precise function of the FA proteins in genome maintenance remains unclear. Here we report that C. elegans FANCD2 (fcd-2) is dispensable for normal meiotic recombination but is required in crossover defective mutants to prevent illegitimate repair of meiotic breaks by nonhomologous end joining (NHEJ). In mitotic cells, we show that DNA repair defects of C. elegans fcd-2 mutants and FA-deficient human cells are significantly suppressed by eliminating NHEJ. Moreover, NHEJ factors are inappropriately recruited to sites of replication stress in the absence of FANCD2. Our findings are consistent with the interpretation that FA results from the promiscuous action of NHEJ during DNA repair. We propose that a critical function of the FA pathway is to channel lesions into accurate, as opposed to error-prone, repair pathways.