Ikura Masae, Furuya Kanji, Matsuda Shun, Matsuda Ryo, Shima Hiroki, Adachi Jun, Matsuda Tomonari, Shiraki Takuma, Ikura Tsuyoshi
Laboratory of Chromatin Regulatory Network, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Kyoto, Japan.
Department of Radiation Systems, Radiation Biology Center, Kyoto University, Kyoto, Japan.
Mol Cell Biol. 2015 Dec;35(24):4147-57. doi: 10.1128/MCB.00757-15. Epub 2015 Oct 5.
The association and dissociation of DNA damage response (DDR) factors with damaged chromatin occurs dynamically, which is crucial for the activation of DDR signaling in a spatiotemporal manner. We previously showed that the TIP60 histone acetyltransferase complex acetylates histone H2AX, to facilitate H2AX exchange at sites of DNA damage. However, it remained unclear how the acetylation of histone H2AX by TIP60 is related to the DDR signaling. We found that the acetylation but not the phosphorylation of H2AX is essential for the turnover of NBS1 on damaged chromatin. The loss of H2AX acetylation at Lys 5 by TIP60 in cells disturbed the accumulation of NBS1 at sites of DNA damage. Although the phosphorylation of H2AX is also reportedly required for the retention of NBS1 at damage sites, our data indicated that the acetylation-dependent NBS1 turnover by TIP60 on damaged chromatin restricts the dispersal of NBS1 foci from the sites of DNA damage. These findings indicate the importance of the acetylation-dependent dynamic binding of NBS1 to damaged chromatin, created by histone H2AX exchange, for the proper accumulation of NBS1 at DNA damage sites.
DNA损伤反应（DDR）因子与受损染色质的结合和解离是动态发生的，这对于DDR信号在时空上的激活至关重要。我们之前表明，TIP60组蛋白乙酰转移酶复合物使组蛋白H2AX乙酰化，以促进DNA损伤位点处H2AX的交换。然而，TIP60对组蛋白H2AX的乙酰化与DDR信号之间的关系仍不清楚。我们发现H2AX的乙酰化而非磷酸化对于NBS1在受损染色质上的周转至关重要。细胞中TIP60介导的H2AX第5位赖氨酸乙酰化缺失扰乱了NBS1在DNA损伤位点的积累。尽管据报道H2AX的磷酸化对于NBS1在损伤位点的保留也是必需的，但我们的数据表明，TIP60在受损染色质上通过乙酰化依赖的方式使NBS1周转，限制了NBS1焦点从DNA损伤位点的扩散。这些发现表明，由组蛋白H2AX交换产生的NBS1与受损染色质的乙酰化依赖的动态结合，对于NBS1在DNA损伤位点的正确积累至关重要。
