Structure of the processive human Pol δ holoenzyme

Nat Commun. 2020 Feb 28;11(1):1109. doi: 10.1038/s41467-020-14898-6.


In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ-DNA-PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ's activity in replicating the human genome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Catalytic Domain
  • Cryoelectron Microscopy
  • DNA / metabolism
  • DNA Polymerase III / chemistry*
  • DNA Polymerase III / genetics
  • DNA Polymerase III / metabolism*
  • DNA Replication
  • Flap Endonucleases / chemistry
  • Flap Endonucleases / metabolism
  • Holoenzymes
  • Humans
  • Models, Molecular
  • Proliferating Cell Nuclear Antigen / chemistry
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Binding
  • Protein Subunits
  • Structure-Activity Relationship


  • Holoenzymes
  • PCNA protein, human
  • Proliferating Cell Nuclear Antigen
  • Protein Subunits
  • DNA
  • DNA Polymerase III
  • Flap Endonucleases
  • FEN1 protein, human