The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2.
The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2.
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DOI：
10.1038/ncomms12124
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发表时间：
2016-07-13
影响因子：
16.6
通讯作者：
Cohn MA
中科院分区：
文献类型：
--
作者：
Liang CC;Li Z;Lopez-Martinez D;Nicholson WV;Vénien-Bryan C;Cohn MA
范可尼贫血（Fanconi anemia， FA）通路对DNA链间交联（interstrand交联，ICL）修复具有重要意义。FANCD2-FANCI复合体是该通路的核心，并依赖于其单泛素化定位到icl。这个复合体是在关键的单泛素化之前还是之后被招募的，这仍然是难以捉摸的。在这里，我们通过获得低温电镜结构首次报道了人类FANCD2-FANCI复合物的结构。该复合体包含一个内腔，大到足以容纳双链DNA螺旋，以及一个突出的塔结构域。在一些FA患者中观察到Tower结构域的致病突变。我们的工作表明，复合体被招募到一个停滞的复制叉上，作为激活单泛素化事件的触发器。综上所述，我们的研究结果揭示了FANCD2-FANCI复合物如何激活FA通路的机制，并解释了Tower结构域突变的FA患者的潜在分子缺陷。FANCD2和FANCI是范可尼贫血DNA损伤修复途径的重要组成部分。在这里，作者展示了FANCD2-FANCI复合体的低温电镜结构，提供了对复合体如何被招募来阻止复制分叉的见解。
The Fanconi anaemia (FA) pathway is important for the repair of DNA interstrand crosslinks (ICL). The FANCD2–FANCI complex is central to the pathway, and localizes to ICLs dependent on its monoubiquitination. It has remained elusive whether the complex is recruited before or after the critical monoubiquitination. Here, we report the first structural insight into the human FANCD2–FANCI complex by obtaining the cryo-EM structure. The complex contains an inner cavity, large enough to accommodate a double-stranded DNA helix, as well as a protruding Tower domain. Disease-causing mutations in the Tower domain are observed in several FA patients. Our work reveals that recruitment of the complex to a stalled replication fork serves as the trigger for the activating monoubiquitination event. Taken together, our results uncover the mechanism of how the FANCD2–FANCI complex activates the FA pathway, and explains the underlying molecular defect in FA patients with mutations in the Tower domain. FANCD2 and FANCI are essential components of the Fanconi anaemia DNA damage repair pathway. Here the authors present the cryo-EM structure of the FANCD2-FANCI complex, providing insight into how the complex is recruited to stalled replication forks.