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首页> 外文期刊>Molecular and Cellular Biology >FANCD2-Controlled Chromatin Access of the Fanconi-Associated Nuclease FAN1 Is Crucial for the Recovery of Stalled Replication Forks
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FANCD2-Controlled Chromatin Access of the Fanconi-Associated Nuclease FAN1 Is Crucial for the Recovery of Stalled Replication Forks

机译：Fanconi相关的核酸酶FAN1的FANCD2控制的染色质访问对于停滞的复制叉的恢复至关重要。

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Fanconi anemia (FA) is a cancer predisposition syndrome characterized by cellular hypersensitivity to DNA interstrand cross-links (ICLs). Within the FA pathway, an upstream core complex monoubiquitinates and recruits the FANCD2 protein to ICLs on chromatin. Ensuing DNA repair involves the Fanconi-associated nuclease 1 (FAN1), which interacts selectively with monoubiquitinated FANCD2 (FANCD2Ub) at ICLs. Importantly, FANCD2 has additional independent functions: it binds chromatin and coordinates the restart of aphidicolin (APH)-stalled replication forks in concert with the BLM helicase, while protecting forks from nucleolytic degradation by MRE11. We identified FAN1 as a new crucial replication fork recovery factor. FAN1 joins the BLM-FANCD2 complex following APH-mediated fork stalling in a manner dependent on MRE11 and FANCD2, followed by FAN1 nuclease-mediated fork restart. Surprisingly, APH-induced activation and chromatin recruitment of FAN1 occur independently of the FA core complex or the FAN1 UBZ domain, indicating that the FANCD2Ub isoform is dispensable for functional FANCD2-FAN1 cross talk during stalled fork recovery. In the absence of FANCD2, MRE11 exonuclease-promoted access of FAN1 to stalled forks results in severe FAN1-mediated nucleolytic degradation of nascent DNA strands. Thus, FAN1 nuclease activity at stalled replication forks requires tight regulation: too little inhibits fork restart, whereas too much causes fork degradation.
机译：范可尼贫血（FA）是一种癌症易感综合征，其特征是细胞对DNA链间交联（ICL）过敏。在FA途径中，上游核心复合物单泛素化并将FANCD2蛋白募集到染色质上的IC​​L。随后的DNA修复涉及与Fanconi相关的核酸酶1（FAN1），该酶与ICL处的单泛素化FANCD2（FANCD2 Ub ）选择性相互作用。重要的是，FANCD2具有附加的独立功能：它与BLM解旋酶结合染色质并协调Aphidicolin（APH）固定的复制叉的重启，同时保护叉不受MRE11的核酸降解。我们将FAN1确定为新的关键复制叉恢复因子。在APH介导的分叉停止后，FAN1以依赖于MRE11和FANCD2的方式加入BLM-FANCD2复合体，然后由FAN1核酸酶介导的分叉重新启动。出乎意料的是，APH诱导的FAN1激活和染色质募集独立于FA核心复合物或FAN1 UBZ结构域发生，表明FANCD2 Ub 同工型对于失速叉恢复过程中功能性FANCD2-FAN1串扰是必不可少的。在缺少FANCD2的情况下，MRE11核酸外切酶促进的FAN1进入停滞的叉子导致严重的FAN1介导的新生DNA链的核酸降解。因此，停滞的复制叉中的FAN1核酸酶活性需要严格调节：过少会抑制叉重启，而过多则会导致叉降解。

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