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The Eukaryotic Mcm2-7 Replicative Helicase

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The Eukaryotic Replisome: a Guide to Protein Structure and Function

Part of the book series: Subcellular Biochemistry ((SCBI,volume 62))

Abstract

In eukaryotes, the Mcm2-7 complex forms the core of the replicative helicase – the molecular motor that uses ATP binding and hydrolysis to fuel the unwinding of double-stranded DNA at the replication fork. Although it is a toroidal hexameric helicase superficially resembling better-studied homohexameric helicases from prokaryotes and viruses, Mcm2-7 is the only known helicase formed from six unique and essential subunits. Recent biochemical and structural analyses of both Mcm2-7 and a higher-order complex containing additional activator proteins (the CMG complex) shed light on the reason behind this unique subunit assembly: whereas only a limited number of specific ATPase active sites are needed for DNA unwinding, one particular ATPase active site has evolved to form a reversible discontinuity (gate) in the toroidal complex. The activation of Mcm2-7 helicase during S-phase requires physical association of the accessory proteins Cdc45 and GINS; structural data suggest that these accessory factors activate DNA unwinding through closure of the Mcm2-7 gate. Moreover, studies capitalizing on advances in the biochemical reconstitution of eukaryotic DNA replication demonstrate that Mcm2-7 loads onto origins during initiation as a double hexamer, yet does not act as a double-stranded DNA pump during elongation.

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Acknowledgements

We express our gratitude to N. Simon, M. Bochman and E. Tsai for their critical reading and insightful comments on the manuscript. This work is supported by IRO1GM83985 grant from NIH.

Note added in proof Using the Xenopus DNA replication system and single-molecule experiments utilizing strand-specific roadblocks, Fu et al. (Cell 146, 931-941, 2011) recently demonstrated that the CMG helicase can track along single-stranded DNA in a 3’-5’ direction on the leading strand while selectively excluding the lagging strand template. While a dsDNA pump would effectively stall regardless of the placement of the obstruction on either strand, a strand-specific translocation mechanism would selectively allow bypass of an obstruction one of the two strands. By presenting strong experimental evidence in favor of the latter scenario, Fu et al. validate the steric exclusion model of DNA unwinding by the Mcm2-7 helicase.

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  1. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Sriram Vijayraghavan & Anthony Schwacha

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  1. Sriram Vijayraghavan
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Correspondence to Anthony Schwacha .

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    Stuart MacNeill

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Vijayraghavan, S., Schwacha, A. (2012). The Eukaryotic Mcm2-7 Replicative Helicase. In: MacNeill, S. (eds) The Eukaryotic Replisome: a Guide to Protein Structure and Function. Subcellular Biochemistry, vol 62. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4572-8_7

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