Chen Xuefeng, Niu Hengyao, Yu Yang, Wang Jingjing, Zhu Shuangyi, Zhou Jianjie, Papusha Alma, Cui Dandan, Pan Xuewen, Kwon Youngho, Sung Patrick, Ira Grzegorz
College of Life Sciences and Institute for Advanced Studies, Wuhan University, Wuhan, Hubei 40072, China
Department of Biochemistry and Biophysics, Yale University School of Medicine, New Haven, CT, USA.
Nucleic Acids Res. 2016 Apr 7;44(6):2742-53. doi: 10.1093/nar/gkv1544. Epub 2016 Jan 21.
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.
DNA双链断裂（DSBs）是挑战基因组完整性的最具细胞毒性的DNA损伤类型之一。细胞周期蛋白依赖性激酶Cdk1的活性对于通过同源重组进行的DSB修复以及DNA损伤信号传导至关重要。在这里，我们确定Fun30染色质重塑因子是Cdk1的一个新靶点。Fun30在丝氨酸28处被Cdk1磷酸化，以刺激其在DNA损伤反应中的功能，包括DSB末端的切除。重要的是，DNA损伤时Fun30-S28的Cdk1依赖性磷酸化增加，并且需要将Fun30募集到DSBs，这表明磷酸化在DNA损伤处原位增加。一致地，我们发现Cdk1和多种细胞周期蛋白在DSBs处高度富集，并且Cdk1以及细胞周期蛋白Clb2和Clb5的募集确保了最佳的Fun30磷酸化和检查点激活。我们提出，Cdk1-细胞周期蛋白复合物在DSBs处的富集作为一种机制，用于增强对DNA损伤反应蛋白活性的靶向和调节。
