Structure of DNA-CMG-Pol epsilon elucidates the roles of the non-catalytic polymerase modules in the eukaryotic replisome

Panchali Goswami, Ferdos Abid Ali, Max E. Douglas, Julia Locke, Andrew Purkiss, Agnieszka Janska, Patrik Eickhoff, Anne Early, Andrea Nans, Alan M. C. Cheung, John F. X. Diffley and Alessandro Costa ()
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Panchali Goswami: The Francis Crick Institute
Ferdos Abid Ali: The Francis Crick Institute
Max E. Douglas: The Francis Crick Institute
Julia Locke: The Francis Crick Institute
Andrew Purkiss: The Francis Crick Institute
Agnieszka Janska: The Francis Crick Institute
Patrik Eickhoff: The Francis Crick Institute
Anne Early: The Francis Crick Institute
Andrea Nans: The Francis Crick Institute
Alan M. C. Cheung: University College London
John F. X. Diffley: The Francis Crick Institute
Alessandro Costa: The Francis Crick Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Eukaryotic origin firing depends on assembly of the Cdc45-MCM-GINS (CMG) helicase. A key step is the recruitment of GINS that requires the leading-strand polymerase Pol epsilon, composed of Pol2, Dpb2, Dpb3, Dpb4. While a truncation of the catalytic N-terminal Pol2 supports cell division, Dpb2 and C-terminal Pol2 (C-Pol2) are essential for viability. Dpb2 and C-Pol2 are non-catalytic modules, shown or predicted to be related to an exonuclease and DNA polymerase, respectively. Here, we present the cryo-EM structure of the isolated C-Pol2/Dpb2 heterodimer, revealing that C-Pol2 contains a DNA polymerase fold. We also present the structure of CMG/C-Pol2/Dpb2 on a DNA fork, and find that polymerase binding changes both the helicase structure and fork-junction engagement. Inter-subunit contacts that keep the helicase-polymerase complex together explain several cellular phenotypes. At least some of these contacts are preserved during Pol epsilon-dependent CMG assembly on path to origin firing, as observed with DNA replication reconstituted in vitro.

Date: 2018
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DOI: 10.1038/s41467-018-07417-1

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