20 October 2026
By combining structural and biochemical approaches, Human Technopole researchers revealed how phosphorylation of the protein M18BP1 activates condensin II, a molecular complex that compacts nuclear DNA as cells prepare to divide. Their findings are published in Nature Structural and Molecular Biology.
Once upon a time, a cell formed, and after several rounds of cell divisions, an organism was born.
This is the very beginning of all our stories. Since the day we were conceived, cell division has played a fundamental and defining role in our lives. During this biological process, one cell doubles its genetic material and divides to give rise to two genetically identical daughter cells. To safely distribute the replicated DNA, a highly regulated mechanism called mitosis takes place.
Mitotic onset is defined by a crucial step: the doubled, loose DNA is condensed into compact chromosomes, spatially defined, rod-like structures that can be neatly organised and separated into the two daughter cells. DNA compaction is a strictly controlled process, as its effective and timely occurrence is necessary for the success of cell division. Gaining a comprehensive view of this fundamental mechanism is one of the research goals of the Vannini Group at Human Technopole.
Among the crucial players involved in the regulation of DNA compaction is a nuclear protein called condensin II, whose activation must be tightly orchestrated to prevent premature chromosome formation. In a study published in 2025 in Molecular Cell, the Vannini Group identified the protein M18BP1 as an essential factor in this multistep process. At mitotic onset, M18BP1 gets phosphorylated (M18BP1P) and binds to condensin II to activate it, thus triggering DNA compaction. However, the mechanism behind this molecular switch remains unclear.
Building on their previous findings, the researchers embraced the challenge of fully solving this riddle with a combination of biochemical and structural approaches. First, they applied single-molecule imaging to visualise how condensin II interacts with DNA in the presence or absence of M18BP1P and observed two DNA compaction mechanisms: individual condensin II complexes reversibly bind and compact DNA through a mechanism dependent on the consumption of ATP, the cellular energy currency; additionally, pre-formed complexes between condensin II and M18BP1P form large clusters on DNA and induce its persistent compaction, without consuming ATP.
The group also performed cryo-electron microscopy (cryo-EM) – an imaging technique where samples are frozen and photographed at multiple angles to obtain a 3D representation of the original structure – to visualise the conformational changes undergone by condensin II in complex with M18BP1P before and after DNA binding.
“A major challenge was optimising cryo-EM samples, as the large size and structural flexibility of condensin II complicated high-resolution structure determination,” explains Alessandro Borsellini, a former postdoctoral researcher in the Vannini Group and first author of the study. “Nearly two years of iterative optimisation and single-particle analysis ultimately enabled us to resolve structures linking M18BP1-induced rearrangements to condensin II activation.”
Indeed, the resolved cryo-EM structures revealed that isolated condensin II adopts an inactive conformation in which its DNA binding pocket is blocked in a state unable to accommodate DNA. Upon M18BP1P binding, condensin II undergoes dramatic rearrangements and transitions from the inactive state to one fit for DNA engagement. Finally, when the M18BP1P-condensin II complexes bind to DNA, a conformation of the DNA binding pocket of condensin II reminiscent of a closed gate stably locks the DNA in position and initiates its compaction.
Together, these results suggest that M18BP1P binding is the main mechanism that drives condensin II activation, triggering the molecular switch that turns loose DNA into chromosomes.
Reflecting on the study, Alessandro Vannini, senior author and Head of the Structural Biology Research Centre at Human Technopole, says: “After overcoming technical challenges to integrate structural and functional observations, we were able to provide a mechanistic understanding of how M18BP1 regulates condensin II activity.”
By elucidating the key steps leading to condensin II activation, the researchers revealed novel insights into chromosome formation, a crucial event in the eukaryotic cell cycle. The newly gained knowledge lays the foundation for future studies aimed at assessing the consequences of potential disruptions of this mechanism on DNA compaction and chromosome stability to further unravel the role of such fundamental molecular processes in health and disease.
In a Research Briefing accompanying the main article, the authors recapitulate their study and disclose some behind-the-scenes moments of their discovery.
Borsellini, A., Chamera, S., Cecatiello, V. et al. Mechanism of M18BP1-mediated activation of condensin II for mitotic DNA compaction. Nat Struct Mol Biol (2026). https://doi.org/10.1038/s41594-026-01902-8
Cover illustration: Atomic model of human condensin II fitted into the cryo-EM density map, shown as a semi-transparent grey surface.
Image: Schematic representation of the transition of human condensin II from an inhibited to an activated state upon interaction with M18BP1. In the inhibited state (left), condensin II adopts a compact architecture. Recruitment of M18BP1 promotes structural rearrangements, resulting in a more open conformation capable of interacting with DNA (right). Enlarged views show the corresponding experimental cryo-EM maps.
