Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.
Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.
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DOI：
10.1126/science.aad5634
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发表时间：
2016-02-19
期刊：
影响因子：
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通讯作者：
Rouse J
中科院分区：
文献类型：
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作者：
Lachaud C;Moreno A;Marchesi F;Toth R;Blow JJ;Rouse J
Fancd 2的单泛素化对于修复DNA链间交联（ICL）是必不可少的，但其潜在机制尚不清楚。Fan 1核酸酶也是ICL修复所需的，通过泛素化（Ub）-Fancd 2募集到ICL。这可以在原则上解释Ub-Fancd 2如何促进ICL修复，但我们发现Ub-Fancd 2对Fan 1的招募对于ICL修复是不必要的。相反，Fan 1的募集和活性抑制了DNA复制叉的进展，并在DNA复制叉停滞时防止染色体异常的发生。因此，Fan 1核酸酶缺陷型敲入小鼠是癌症易感的。此外，我们还发现，高危胰腺癌中的Fan 1变异体消除了Ub-Fancd 2的招募，并在不影响ICL修复的情况下引起遗传不稳定性。因此，Fan 1募集能够处理停滞的分叉，这对基因组稳定性和健康至关重要。
Mono-ubiquitination of Fancd2 is essential for repairing DNA inter-strand crosslinks (ICLs) but the underlying mechanisms are unclear. The Fan1 nuclease, also required for ICL repair, is recruited to ICLs by ubiquitinated (Ub)-Fancd2. This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair. Instead Fan1 recruitment – and activity –restrains DNA replication fork progression, and prevent chromosome abnormalities from occurring, when DNA replication forks stall. Accordingly, Fan1 nuclease-defective knockin mice are cancer-prone. Moreover, we show that a Fan1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-Fancd2, and causes genetic instability without affecting ICL repair. Therefore, Fan1 recruitment enables processing of stalled forks that is essential for genome stability and health.