Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate.

Nature Communications
Ferdos Abid AliAlessandro Costa

Abstract

The Cdc45-MCM-GINS (CMG) helicase unwinds DNA during the elongation step of eukaryotic genome duplication and this process depends on the MCM ATPase function. Whether CMG translocation occurs on single- or double-stranded DNA and how ATP hydrolysis drives DNA unwinding remain open questions. Here we use cryo-electron microscopy to describe two subnanometre resolution structures of the CMG helicase trapped on a DNA fork. In the predominant state, the ring-shaped C-terminal ATPase of MCM is compact and contacts single-stranded DNA, via a set of pre-sensor 1 hairpins that spiral around the translocation substrate. In the second state, the ATPase module is relaxed and apparently substrate free, while DNA intimately contacts the downstream amino-terminal tier of the MCM motor ring. These results, supported by single-molecule FRET measurements, lead us to suggest a replication fork unwinding mechanism whereby the N-terminal and AAA+ tiers of the MCM work in concert to translocate on single-stranded DNA.

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Datasets Mentioned

BETA
EMD-3321

Methods Mentioned

BETA
FRET
FCS

Software Mentioned

ResMap
CTFFIND4
PyMOL Molecular Graphics System
UCSF Chimera
PDBe FSC
RELION
EMAN2
XMIPP3
SerialEM
CTFFIND3

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