New publication by the Ulrich lab and associated member Max Reuter on the Mechanisms of MCM2–7 helicase activation and initial DNA melting at near base-pair resolution
Weekes C, Willerding L, Khadayate SP, Liebl K, Mossler A, Montoya A, Rauthe V, Karimi MM, Zacharias M, Ulrich HD, Speck C, Reuter LM (2026) Mechanisms of MCM2–7 helicase activation and initial DNA melting at near base-pair resolution. Nat Commun, doi.org/10.1038/s41467-026-75695-1 Link
Abstract:
During eukaryotic DNA replication initiation, inactive MCM2–7 double-hexamers assembled at replication origins must be converted into two active CMG helicases, yet how this transition is coupled to origin DNA unwinding in vivo remains unclear. Here, we identify a DNA-bound intermediate with an extended genomic footprint that forms during helicase activation. Genome-wide mapping of initial strand separation reveals that DNA unwinding initiates near the N-terminal interface of opposing MCM2–7 hexamers. At these sites, the origin DNA exhibits a conserved AT-rich/GC-rich/AT-rich sequence architecture centred under the helicase complex, which is associated with an elevated DNA melting probability. We further show that restricting hexamer splitting delays release of the Cdc45-loading factor Sld3, demonstrating that mechanical transitions during helicase activation are tightly coupled to complex disassembly. Finally, we provide in vivo evidence that single-stranded DNA is ejected through a specialised DNA exit gate at the Mcm2/5 interface during helicase activation, which is dispensable for ongoing DNA synthesis. Together, these findings establish a mechanistic framework for how replication origins are remodelled to initiate DNA replication and reveal key intermediates and DNA transactions during helicase activation.
Read the full article here: https://www.nature.com/articles/s41467-026-75695-1
