Constitutive role of the Fanconi anemia D2 gene in the replication stress response
Constitutive role of the Fanconi anemia D2 gene in the replication stress response
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DOI：
10.1074/jbc.m117.814780
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发表时间：
2017-10
期刊：
影响因子：
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通讯作者：
Yanyan Tian;Xi Shen;Rui Wang;Naeh L. Klages-Mundt;E. Lynn;Sara K. Martin;Yin Ye;Min Gao;Junjie Chen;K. Schlacher;Lei Li
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文献类型：
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作者：
Yanyan Tian;Xi Shen;Rui Wang;Naeh L. Klages-Mundt;E. Lynn;Sara K. Martin;Yin Ye;Min Gao;Junjie Chen;K. Schlacher;Lei Li
为了应对DNA交联损伤，Fanconi anemia （FA）核心复合体通过单泛素化Fanconi anemia互补组D2 （FANCD2）激活FA通路，启动DNA交联的核分解加工，稳定停滞的复制分叉。考虑到所有经典FA蛋白协同地单泛素化FANCD2，尚不清楚为什么单个经典FA基因的缺失会产生不同的细胞对交联损伤的敏感性。为了解决这个问题，我们建立了FA核心复合物组分和FANCD2的细胞敲除模型，发现FANCD2-null突变体比Fanconi贫血互补组L (FANCL)-null突变体表现出更高水平的自发染色体损伤和对复制阻断病变的超敏反应，这表明FANCD2在缺乏单泛素化的情况下提供了基础水平的DNA保护来对抗内源性病变。FANCD2与泛素化无关的功能可能参与了优化的核分解活性招募，以加工和保护应激复制分叉。我们的研究结果表明，FANCD2在对抗内源性复制应激水平方面具有泛素化无关的作用，这一功能对维持基因组稳定性至关重要。
In response to DNA cross-linking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monoubiquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA cross-links and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiquitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to cross-linking damage. To address this question, we generated cellular knock-out models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination. FANCD2's ubiquitination-independent function is likely involved in optimized recruitment of nucleolytic activities for the processing and protection of stressed replication forks. Our results reveal that FANCD2 has a ubiquitination-independent role in countering endogenous levels of replication stress, a function that is critical for the maintenance of genomic stability.