DNA unwinding mechanism of a eukaryotic replicative CMG helicase

Zuanning Yuan, Roxana Georgescu, Lin Bai, Dan Zhang, Huilin Li () and Michael E. O’Donnell ()
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Zuanning Yuan: Van Andel Institute
Roxana Georgescu: Howard Hughes Medical Institute
Lin Bai: Van Andel Institute
Dan Zhang: The Rockefeller University
Huilin Li: Van Andel Institute
Michael E. O’Donnell: Howard Hughes Medical Institute

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract High-resolution structures have not been reported for replicative helicases at a replication fork at atomic resolution, a prerequisite to understanding the unwinding mechanism. The eukaryotic replicative CMG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the C-tier motor ring behind. The N-tier ring is structurally divided into a zinc finger (ZF) sub-ring followed by the oligosaccharide/oligonucleotide-binding (OB) fold ring. Here we report the cryo-EM structure of CMG on forked DNA at 3.9 Å, revealing that parental DNA enters the ZF sub-ring and strand separation occurs at the bottom of the ZF sub-ring, where the lagging strand is blocked and diverted sideways by OB hairpin-loops of Mcm3, Mcm4, Mcm6, and Mcm7. Thus, instead of employing a specific steric exclusion process, or even a separation pin, unwinding is achieved via a “dam-and-diversion tunnel” mechanism that does not require specific protein-DNA interaction. The C-tier motor ring contains spirally configured PS1 and H2I loops of Mcms 2, 3, 5, 6 that translocate on the spirally-configured leading strand, and thereby pull the preceding DNA segment through the diversion tunnel for strand separation.

Date: 2020
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DOI: 10.1038/s41467-020-14577-6

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