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首页> 外文期刊>Cell discovery. >Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks
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Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks

机译：Bloom综合症促进了FANCM募集到停滞的复制叉中，并促进了DNA链间交联的修复和遍历

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The recruitment of FANCM, a conserved DNA translocase and key component of several DNA repair protein complexes, to replication forks stalled by DNA interstrand crosslinks (ICLs) is a step upstream of the Fanconi anemia (FA) repair and replication traverse pathways of ICLs. However, detection of the FANCM recruitment has been technically challenging so that its mechanism remains exclusive. Here, we successfully observed recruitment of FANCM at stalled forks using a newly developed protocol. We report that the FANCM recruitment depends upon its intrinsic DNA translocase activity, and its DNA-binding partner FAAP24. Moreover, it is dependent on the replication checkpoint kinase, ATR; but is independent of the FA core and FANCD2–FANCI complexes, two essential components of the FA pathway, indicating that the FANCM recruitment occurs downstream of ATR but upstream of the FA pathway. Interestingly, the recruitment of FANCM requires its direct interaction with Bloom syndrome complex composed of BLM helicase, Topoisomerase 3α, RMI1 and RMI2; as well as the helicase activity of BLM. We further show that the FANCM–BLM complex interaction is critical for replication stress-induced FANCM hyperphosphorylation, for normal activation of the FA pathway in response to ICLs, and for efficient traverse of ICLs by the replication machinery. Epistasis studies demonstrate that FANCM and BLM work in the same pathway to promote replication traverse of ICLs. We conclude that FANCM and BLM complex work together at stalled forks to promote both FA repair and replication traverse pathways of ICLs.
机译：将FANCM（一种保守的DNA转移酶和几种DNA修复蛋白复合物的关键成分）招募到由DNA链间交联（ICL）阻滞的复制叉，是ICL的Fanconi贫血（FA）修复和复制遍历途径的上游步骤。但是，检测FANCM招募在技术上一直具有挑战性，因此其机制仍然是排他的。在这里，我们使用新开发的协议成功地观察到在停滞的货叉上招募了FANCM。我们报告说，FANCM募集取决于其固有的DNA转移酶活性及其DNA结合伙伴FAAP24。而且，它依赖于复制检查点激酶ATR。但是，它独立于FA通路的两个基本组成部分FA核心和FANCD2-FANCI复合物，表明FANCM募集发生在ATR下游但FA通路的上游。有趣的是，FANCM的募集需要其与由BLM解旋酶，拓扑异构酶3α，RMI1和RMI2组成的Bloom综合征复合体直接相互作用。以及BLM的解旋酶活性。我们进一步表明，FANCM-BLM复杂的相互作用对于复制应激诱导的FANCM过度磷酸化，FA通路对ICL的正常激活以及复制机制对ICL的有效遍历至关重要。上位性研究表明，FANCM和BLM以相同的途径促进ICL的复制遍历。我们得出的结论是，FANCM和BLM复合体在停滞的叉子上一起工作，以促进ICL的FA修复和复制遍历途径。

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