Borsellini Alessandro, Conti Duccio, Cutts Erin E, Harris Rebecca J, Walstein Kai, Graziadei Andrea, Cecatiello Valentina, Aarts Tom F, Xie Ren, Mazouzi Abdelghani, Sen Sushweta, Hoencamp Claire, Pleuger Richard, Ghetti Sabrina, Oberste-Lehn Lina, Pan Dongqing, Bange Tanja, Haarhuis Judith H I, Perrakis Anastassis, Brummelkamp Thijn R, Rowland Benjamin D, Musacchio Andrea, Vannini Alessandro
Human Technopole, Milan, Italy.
Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Mol Cell. 2025 Jul 17;85(14):2688-2700.e11. doi: 10.1016/j.molcel.2025.06.014. Epub 2025 Jul 3.
Condensin I and II promote the drastic spatial rearrangement of the human genome upon mitotic entry. While condensin II is known to initiate this process in early mitosis, what triggers its activation and loading onto chromatin at this juncture remains unclear. Through genetic and proteomic approaches, we identify MIS18-binding protein 1 (M18BP1), a protein required to maintain centromere identity, as the elusive factor required for condensin II localization to chromatin. M18BP1 directly binds condensin II's CAP-G2 subunit. The condensin II antagonist MCPH1 also binds to CAP-G2 and outcompetes M18BP1 during interphase to maintain the genome in its uncondensed state. A switch from MCPH1 to M18BP1 at mitotic onset activates condensin II, thus promoting proper chromosome condensation. Regulation of this M18BP1-condensin interaction thus determines both the uncondensed state of the interphase genome and its compacted state in mitosis.
凝缩素I和II在有丝分裂开始时促进人类基因组发生剧烈的空间重排。虽然已知凝缩素II在有丝分裂早期启动这一过程，但此时触发其激活并加载到染色质上的因素仍不清楚。通过遗传学和蛋白质组学方法，我们确定了维持着丝粒身份所需的蛋白质MIS18结合蛋白1（M18BP1），它是凝缩素II定位于染色质所需的难以捉摸的因子。M18BP1直接结合凝缩素II的CAP-G2亚基。凝缩素II拮抗剂MCPH1也与CAP-G2结合，并在间期竞争取代M18BP1，以维持基因组处于未浓缩状态。在有丝分裂开始时从MCPH1切换到M18BP1会激活凝缩素II，从而促进染色体的正常凝聚。因此，这种M18BP1-凝缩素相互作用的调节决定了间期基因组的未浓缩状态及其在有丝分裂中的压缩状态。
