In this section
@article{Speck:2026:10.1038/s41467-026-75695-1,
author = {Speck, C and Reuter, M and Weekes, C},
doi = {10.1038/s41467-026-75695-1},
journal = {Nature Communications},
title = {Mechanisms of MCM2-7 helicase activation and initial DNA melting at near base-pair resolution},
url = {http://dx.doi.org/10.1038/s41467-026-75695-1},
year = {2026}
}
TY - JOUR
AB - 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.
AU - Speck,C
AU - Reuter,M
AU - Weekes,C
DO - 10.1038/s41467-026-75695-1
PY - 2026///
SN - 2041-1723
TI - Mechanisms of MCM2-7 helicase activation and initial DNA melting at near base-pair resolution
T2 - Nature Communications
UR - http://dx.doi.org/10.1038/s41467-026-75695-1
ER -