Enrichment of Cdk1-cyclins at DNA double-strand breaks stimulates Fun30 phosphorylation and DNA end resection.
Enrichment of Cdk1-cyclins at DNA double-strand breaks stimulates Fun30 phosphorylation and DNA end resection.
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DNA 双链断裂处的 Cdk1-cyclins 富集会刺激 Fun30 磷酸化和 DNA 末端切除。
DOI：
10.1093/nar/gkv1544
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发表时间：
2016-04-07
影响因子：
14.9
通讯作者：
Ira G
中科院分区：
文献类型：
--
作者：
Chen X;Niu H;Yu Y;Wang J;Zhu S;Zhou J;Papusha A;Cui D;Pan X;Kwon Y;Sung P;Ira G
DNA双链断裂（DSB）是最具细胞毒性的DNA损伤类型之一，挑战基因组的完整性。细胞周期蛋白依赖性激酶Cdk 1的活性对于通过同源重组的DSB修复和DNA损伤信号传导是必需的。在这里，我们确定Fun 30染色质重塑作为Cdk 1的新靶点。Fun 30被丝氨酸28上的Cdk 1磷酸化，以刺激其在DNA损伤反应中的功能，包括切除DSB末端。重要的是，Fun 30-S28的Cdk 1依赖性磷酸化在DNA损伤后增加，并且需要Fun 30募集到DSB，这表明磷酸化在DNA损伤时原位增加。一致地，我们发现Cdk 1和多种细胞周期蛋白在DSB高度富集，并且Cdk 1和细胞周期蛋白Clb 2和Clb 5的募集确保了最佳的Fun 30磷酸化和检查点激活。我们建议，在DSB的Cdk 1-细胞周期蛋白复合物的富集作为一种机制，增强针对性和调节的DNA损伤反应蛋白的活性。
DNA double-strand breaks (DSBs) are one of the most cytotoxic types of DNA lesion challenging genome integrity. The activity of cyclin-dependent kinase Cdk1 is essential for DSB repair by homologous recombination and for DNA damage signaling. Here we identify the Fun30 chromatin remodeler as a new target of Cdk1. Fun30 is phosphorylated by Cdk1 on Serine 28 to stimulate its functions in DNA damage response including resection of DSB ends. Importantly, Cdk1-dependent phosphorylation of Fun30-S28 increases upon DNA damage and requires the recruitment of Fun30 to DSBs, suggesting that phosphorylation increases in situ at the DNA damage. Consistently, we find that Cdk1 and multiple cyclins become highly enriched at DSBs and that the recruitment of Cdk1 and cyclins Clb2 and Clb5 ensures optimal Fun30 phosphorylation and checkpoint activation. We propose that the enrichment of Cdk1-cyclin complexes at DSBs serves as a mechanism for enhanced targeting and modulating of the activity of DNA damage response proteins.