Biomedical Center Munich, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Street 9, 82152 Planegg-Martinsried, Germany.
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mol Cell. 2017 Dec 7;68(5):860-871.e7. doi: 10.1016/j.molcel.2017.11.019.
DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain's interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1's auto-inhibition and activate chromatin remodeling. Our data show that the NAD-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation.
DNA 损伤通过机制触发染色质重塑，这些机制尚未得到很好的理解。致癌基因和染色质重塑因子 ALC1/CHD1L 在体内大量解压缩染色质，但在 DNA 损伤介导的 PARP1 诱导之前处于非活性状态。我们表明，ALC1 宏域与 ATP 酶模块的相互作用介导自动抑制。PARP1 激活抑制这种抑制性相互作用。至关重要的是，自动抑制的释放需要一个多聚 ADP-核糖（PAR）结合宏域。我们鉴定出三 ADP-核糖是一种有效的 PAR 模拟物和合成变构效应物，可破坏 ATP 酶-宏域相互作用，促进无门构象，并激活重塑因子的 ATP 酶。缺乏调节宏域的 ALC1 片段在体内松弛染色质而无需 PARP1 激活。此外，ATP 酶在非 DNA 损伤条件下限制了宏域与 PARP1 的相互作用。体细胞癌症突变破坏了 ALC1 的自动抑制并激活了染色质重塑。我们的数据表明，NAD 代谢物和核酸 PAR 触发 ALC1 驱动染色质松弛。这种致癌基因中的模块化变构作用严格控制其强大的、依赖于 DNA 损伤的激活。
