The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses chromosome translocation during tumorigenesis
The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses chromosome translocation during tumorigenesis
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核骨架蛋白 IFFO1 固定断裂的 DNA 并抑制肿瘤发生过程中的染色体易位
DOI：
10.1038/s41556-019-0388-0
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发表时间：
2019-10-01
影响因子：
21.3
通讯作者：
Xu, Dongyi
中科院分区：
文献类型：
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作者：
Li, Wen;Bai, Xiuzhen;Xu, Dongyi
染色体易位是多种癌症发生和发展的主要原因。然而，这一过程背后的机制仍然知之甚少。在这里，我们鉴定了一个非同源的末端连接蛋白IFFO1，它在结构上与XRCC4形成一个异四聚体。IFFO1被XRCC4招募到DNA损伤部位，并与XLF平行促进DNA双链断裂的修复。有趣的是，IFFO1与层蛋白A/C相互作用，形成内部核骨架。灭活IFFO1或它与XRCC4或lamin A/C的相互作用会增加断端的流动性和染色体易位的频率。重要的是，这种核骨架的破坏是许多类型的癌细胞中染色体易位频率升高的原因。我们的结果显示，在肿瘤发生过程中，Lamin A/C-IFFO1组成的核骨架通过固定断裂的DNA末端来防止染色体易位。
Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C–IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.