Structure of the processive human Pol δ holoenzyme

Claudia Lancey, Muhammad Tehseen, Vlad-Stefan Raducanu, Fahad Rashid, Nekane Merino, Timothy J. Ragan, Christos G. Savva, Manal S. Zaher, Afnan Shirbini, Francisco J. Blanco, Samir M. Hamdan () and Alfredo De Biasio ()
Additional contact information
Claudia Lancey: University of Leicester
Muhammad Tehseen: King Abdullah University of Science and Technology
Vlad-Stefan Raducanu: King Abdullah University of Science and Technology
Fahad Rashid: King Abdullah University of Science and Technology
Nekane Merino: CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800
Timothy J. Ragan: University of Leicester
Christos G. Savva: University of Leicester
Manal S. Zaher: King Abdullah University of Science and Technology
Afnan Shirbini: King Abdullah University of Science and Technology
Francisco J. Blanco: CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800
Samir M. Hamdan: King Abdullah University of Science and Technology
Alfredo De Biasio: University of Leicester

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14898-6

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