Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells.
Haploinsufficiency of the Mus81-Eme1 endonuclease activates the intra-S-phase and G2/M checkpoints and promotes rereplication in human cells.
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DOI：
10.1093/nar/gkj495
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发表时间：
2006
影响因子：
14.9
通讯作者：
Miyagawa K
中科院分区：
文献类型：
--
作者：
Hiyama T;Katsura M;Yoshihara T;Ishida M;Kinomura A;Tonda T;Asahara T;Miyagawa K
Mus 81-Eme 1复合物是一种结构特异性核酸内切酶，其优先切割有切口的Holliday连接、3′-瓣状结构和异常复制叉结构。Mus 81 −/−小鼠已被证明表现出自发性染色体畸变，并且在两种模型中的一种中表现出癌症易感性。然而，其在染色体完整性中作用的分子机制在很大程度上是未知的。为了阐明Mus 81在人类细胞中的作用，我们通过基因打靶的方法在人类结肠癌细胞系HCT 116中删除了该基因。在这里，我们证明了Mus 81赋予对DNA交联剂的抗性和对其他DNA损伤剂的轻微抗性。Mus 81缺陷通过ATM-Chk 1/Chk 2途径自发地促进染色体损伤，例如断裂和激活S期内检查点。此外，Mus 81缺陷通过ATM-Chk 2途径激活G2/M检查点并促进DNA再复制。增加的再复制被Cdk 1的异位表达逆转。Mus 81或Eme 1的单倍不足也导致类似的表型。这些发现表明，响应DNA双链断裂的检查点通路的复杂网络可能参与与Mus 81或Eme 1缺陷相关的一些表型。
The Mus81–Eme1 complex is a structure-specific endonuclease that preferentially cleaves nicked Holliday junctions, 3′-flap structures and aberrant replication fork structures. Mus81−/− mice have been shown to exhibit spontaneous chromosomal aberrations and, in one of two models, a predisposition to cancers. The molecular mechanisms underlying its role in chromosome integrity, however, are largely unknown. To clarify the role of Mus81 in human cells, we deleted the gene in the human colon cancer cell line HCT116 by gene targeting. Here we demonstrate that Mus81 confers resistance to DNA crosslinking agents and slight resistance to other DNA-damaging agents. Mus81 deficiency spontaneously promotes chromosome damage such as breaks and activates the intra-S-phase checkpoint through the ATM-Chk1/Chk2 pathways. Furthermore, Mus81 deficiency activates the G2/M checkpoint through the ATM-Chk2 pathway and promotes DNA rereplication. Increased rereplication is reversed by the ectopic expression of Cdk1. Haploinsufficiency of Mus81 or Eme1 also causes similar phenotypes. These findings suggest that a complex network of the checkpoint pathways that respond to DNA double-strand breaks may participate in some of the phenotypes associated with Mus81 or Eme1 deficiency.
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