The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Mol Cell. 2018 Nov 15;72(4):625-635.e4. doi: 10.1016/j.molcel.2018.09.023. Epub 2018 Oct 25.
In response to genotoxic stress, cells activate a signaling cascade known as the DNA damage checkpoint (DDC) that leads to a temporary cell cycle arrest and activation of DNA repair mechanisms. Because persistent DDC activation compromises cell viability, this process must be tightly regulated. However, despite its importance, the mechanisms regulating DDC recovery are not completely understood. Here, we identify a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of H4 threonine 80 (H4T80ph), and show that it triggers checkpoint inactivation. H4T80ph is critical for cell survival to DNA damage, and its absence causes impaired DDC recovery and persistent cell cycle arrest. We show that, in response to genotoxic stress, p21-activated kinase Cla4 phosphorylates H4T80 to recruit Rtt107 to sites of DNA damage. Rtt107 displaces the checkpoint adaptor Rad9, thereby interrupting the checkpoint-signaling cascade. Collectively, our results indicate that H4T80ph regulates DDC recovery.
在应对遗传毒性应激时，细胞会激活一种被称为 DNA 损伤检查点（DDC）的信号级联反应，导致细胞周期暂时停滞，并激活 DNA 修复机制。由于持续的 DDC 激活会损害细胞活力，因此必须对这一过程进行严格的调控。然而，尽管其意义重大，但调节 DDC 恢复的机制尚不完全清楚。在这里，我们在酿酒酵母中鉴定出一种受 DNA 损伤调控的组蛋白修饰，即 H4 丝氨酸 80 的磷酸化（H4T80ph），并表明它触发了检查点失活。H4T80ph 对细胞在 DNA 损伤时的存活至关重要，其缺失会导致 DDC 恢复受损和细胞周期持续停滞。我们发现，在应对遗传毒性应激时，p21 激活激酶 Cla4 磷酸化 H4T80 以募集 Rtt107 到 DNA 损伤部位。Rtt107 取代检查点衔接蛋白 Rad9，从而中断检查点信号级联反应。总的来说，我们的研究结果表明，H4T80ph 调节 DDC 的恢复。
