Cryo-EM and single molecule visualization unravel the role of humancondensin II activation by M18BP1 in driving DNA compaction

DNA compaction by human condensin II is crucial for the correct organization of mitotic chromosomes. Mitotic activation of condensin II is a multi-layered 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. 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 thus allowing stable DNA binding and DNA compaction. Beyond the ATP-driven activity of isolated condensin II complexes on DNA, we observe the emergence of multimeric species that withstand the forces applied by optical tweezers, highlighting the contribution of condensin II protein-protein interactions to the mechanical reinforcement of mitotic chromosomes.