Hu Pengjing, Sun Jingxi, Sun Hongyao, Chen Kangjing, Sia Youyang, Xia Xian, Xi Qiaoran, Chen Zhucheng
MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing, P.R. China.
Tsinghua-Peking Joint Center for Life Sciences, Beijing, P.R. China.
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09100-0.
Chromatin remodellers are pivotal in the regulation of nucleosome dynamics in cells, and they are important for chromatin packaging, transcription, replication and DNA repair. Here we show that the human chromatin remodeller SMARCAD1 exhibits a substrate preference for subnucleosomal particles over the canonical nucleosome. Cryo-electron microscopy structures of SMARCAD1 bound to the nucleosome and hexasome provide mechanistic insights into the substrate selectivity. SMARCAD1 binds to the hexasome through multiple family-specific elements that are essential for the functions in vitro and in cells. The enzyme binds to the canonical nucleosome in an inactive conformation, which accounts for its diminished activity towards the nucleosome. Notably, the histone chaperone FACT complex acts synergistically with H2A-H2B to promote the activity of SMARCAD1 in nucleosome remodelling. Together, our findings reveal an avenue for chromatin regulation, whereby subnucleosomes are remodelled through an ATP-dependent process.
染色质重塑因子在细胞中核小体动力学的调控中起关键作用，对染色质包装、转录、复制和DNA修复都很重要。我们在此表明，人类染色质重塑因子SMARCAD1对亚核小体颗粒的底物偏好高于典型核小体。结合核小体和六聚体的SMARCAD1的冷冻电镜结构为底物选择性提供了机制上的见解。SMARCAD1通过多个家族特异性元件与六聚体结合，这些元件对体外和细胞内的功能至关重要。该酶以无活性构象结合典型核小体，这解释了其对核小体活性降低的原因。值得注意的是，组蛋白伴侣FACT复合物与H2A-H2B协同作用，促进SMARCAD1在核小体重塑中的活性。总之，我们的发现揭示了一种染色质调控途径，即通过ATP依赖过程对亚核小体进行重塑。
