FANCJ helicase mutations are known to cause hereditary breast and ovarian cancers as well as bone marrow failure syndrome Fanconi anemia. FANCJ plays an important role in the repair of DNA inter-strand crosslinks and DNA double-strand breaks (DSBs) by homologous recombination (HR). Nonetheless, the molecular mechanism by which FANCJ controls HR mediated DSB repair is obscure. Here, we show that FANCJ promotes DNA end resection by recruiting CtIP to the sites of DSBs. This recruitment of CtIP is dependent on FANCJ K1249 acetylation. Notably, FANCJ acetylation is dependent on FANCJ S990 phosphorylation by CDK. The CDK mediated phosphorylation of FANCJ independently facilitates its interaction with BRCA1 at damaged DNA sites and promotes DNA end resection by CtIP recruitment. Strikingly, mutational studies reveal that ATP binding competent but hydrolysis deficient FANCJ partially supports end resection, indicating that in addition to the scaffolding role of FANCJ in CtIP recruitment, its helicase activity is important for promoting end resection. Together, these data unravel a novel function of FANCJ helicase in DNA end resection and provide mechanistic insights into its role in repairing DSBs by HR and in genome maintenance.

中文翻译：

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FANCJ解旋酶通过促进CtIP募集到DNA双链断裂来促进DNA末端切除。

已知FANCJ解旋酶突变会导致遗传性乳腺癌和卵巢癌，以及骨髓衰竭综合征Fanconi贫血。FANCJ在通过同源重组（HR）修复DNA链间交联和DNA双链断裂（DSB）中起重要作用。尽管如此，FANCJ控制HR介导的DSB修复的分子机制仍然不清楚。在这里，我们显示FANCJ通过将CtIP募集到DSBs的位点来促进DNA末端切除。CtIP的募集依赖于FANCJ K1249乙酰化。值得注意的是，FANCJ乙酰化取决于CDK对FANCJ S990的磷酸化作用。CDK介导的FANCJ磷酸化独立促进其与受损DNA位点上的BRCA1相互作用，并通过CtIP募集促进DNA末端切除。惊人地 突变研究表明，ATP结合能力强但缺乏水解的FANCJ部分支持末端切除，这表明，除了FANCJ在CtIP募集中的脚手架作用外，其解旋酶活性对于促进末端切除也很重要。总之，这些数据揭示了FANCJ解旋酶在DNA末端切除中的新功能，并提供了有关其在HR修复DSB中的作用和基因组维护中的机制的见解。