Mechanism of M18BP1-mediated activation of condensin II for mitotic DNA compaction

DNA compaction by human condensin II is crucial for the correct organization of mitotic chromosomes. Mitotic activation of condensin II is a multilayered process, controlled mainly by the opposing activity of the MCPH1 and M18BP1 proteins, acting as an interphase inhibitor and a mitotic activator, respectively. Mitotic phosphorylation favors M18BP1 binding to condensin II, resulting in effective and timely chromosome compaction. However, the molecular mechanisms underlying condensin II activation in driving DNA compaction remain uncharacterized. Here, combining cryo-electron microscopy with single-molecule imaging, we unravel the mechanism of condensin II activation by M18BP1 and elucidate their role in DNA compaction. The specific interaction with phosphorylated M18BP1 induces conformational changes in the condensin II complex, relieving an autoinhibitory conformation and allowing stable DNA binding and DNA compaction. Beyond the activity of isolated condensin II complexes on DNA, we observe the emergence of multimeric species that withstand the forces applied by optical tweezers, suggesting that condensin II multimerization might contribute to the mechanical reinforcement of mitotic chromosomes. Here, the authors show that phosphorylated M18BP1 activates condensin II by relieving an autoinhibitory interface, enabling stable DNA binding and compaction. Additionally, the M18BP1–condensin II complex forms clusters that might mechanically reinforce mitotic chromosomes.