Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, 75124 Uppsala, Sweden.
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Cell Rep. 2020 Dec 22;33(12):108529. doi: 10.1016/j.celrep.2020.108529.
Upon DNA damage, the ALC1/CHD1L nucleosome remodeling enzyme (remodeler) is activated by binding to poly(ADP-ribose). How activated ALC1 recognizes the nucleosome, as well as how this recognition is coupled to remodeling, is unknown. Here, we show that remodeling by ALC1 requires a wild-type acidic patch on the entry side of the nucleosome. The cryo-electron microscopy structure of a nucleosome-ALC1 linker complex reveals a regulatory linker segment that binds to the acidic patch. Mutations within this interface alter the dynamics of ALC1 recruitment to DNA damage and impede the ATPase and remodeling activities of ALC1. Full activation requires acidic patch-linker segment interactions that tether the remodeler to the nucleosome and couple ATP hydrolysis to nucleosome mobilization. Upon DNA damage, such a requirement may be used to modulate ALC1 activity via changes in the nucleosome acidic patches.
在 DNA 损伤后，ALC1/CHD1L 核小体重塑酶（重塑酶）通过与聚 ADP-核糖结合而被激活。激活的 ALC1 如何识别核小体，以及这种识别如何与重塑相关联，目前尚不清楚。在这里，我们表明，ALC1 的重塑需要核小体入口侧的野生型酸性斑。核小体-ALC1 连接体复合物的低温电子显微镜结构揭示了一个调节连接体片段，该片段与酸性斑结合。该界面内的突变会改变 ALC1 募集到 DNA 损伤的动力学，并阻碍 ALC1 的 ATP 酶和重塑活性。完全激活需要酸性斑-连接体片段相互作用，将重塑酶固定在核小体上，并将 ATP 水解与核小体运动偶联。在 DNA 损伤后，这种要求可能通过核小体酸性斑的变化来调节 ALC1 的活性。
