HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression
HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression
复制标题
DOI：
10.1158/0008-5472.can-11-0385
复制
发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Ohta, Tomohiko
中科院分区：
文献类型：
--
作者：
Izawa, Naoki;Wu, Wenwen;Ohta, Tomohiko
DNA复制、重组和修复是高度相互关联的过程，其破坏必须在癌症中协调。HERC 2是同源重组修复所需的大HECT蛋白，是靶向乳腺癌抑制因子BRCA 1降解的E3泛素连接酶。在这里，我们表明HERC 2是DNA复制叉复合物的一个组成部分，在DNA延伸和起点发射中起着关键作用。在BRCA 1存在的情况下，内源性HERC 2与Claspin相互作用，Claspin是G（2）-M检查点激活和复制叉稳定性所必需的蛋白质。Claspin耗竭减缓了S期进展，并且额外的HERC 2耗竭降低了Claspin耗竭的作用。此外，HERC 2与复制叉复合物蛋白相互作用。HERC 2的消耗减轻了Claspin缺陷细胞中缓慢的复制叉进展，抑制了增强的起点放电，并导致MCM 2磷酸化的减少。以HERC 2依赖的方式，用复制抑制剂aphidicolin处理细胞增强MCM 2磷酸化。综上所述，我们的研究结果表明，HERC 2通过促进MCM 2磷酸化来调节DNA复制进程和起点发射。这些发现确立了HERC 2在DNA修复、检查点激活和DNA复制中的关键功能。Cancer Res; 71（17）; 5621-5.（C）2011年《非洲标准化评论》。
DNA replication, recombination, and repair are highly interconnected processes the disruption of which must be coordinated in cancer. HERC2, a large HECT protein required for homologous recombination repair, is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here, we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, endogenous HERC2 interacts with Claspin, a protein essential for G(2)-M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase progression and additional HERC2 depletion reduced the effect of Claspin depletion. In addition, HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing, and led to a decrease in MCM2 phosphorylation. In a HERC2-dependent manner, treatment of cells with replication inhibitor aphidicolin enhanced MCM2 phosphorylation. Taken together, our results suggest that HERC2 regulates DNA replication progression and origin firing by facilitating MCM2 phosphorylation. These findings establish HERC2 as a critical function in DNA repair, checkpoint activation, and DNA replication. Cancer Res; 71(17); 5621-5. (C)2011 AACR.