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Nat Struct Mol Biol. 2019 Oct;26(10):955-962. doi: 10.1038/s41594-019-0305-z. Epub 2019 Oct 3.

Cryo-EM structure and dynamics of eukaryotic DNA polymerase δ holoenzyme.

Author information

1
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. rinku.jain@mssm.edu.
2
Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
3
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
5
Instituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, Leioa, Spain.
6
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
7
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. aneel.aggarwal@mssm.edu.

Abstract

DNA polymerase δ (Polδ) plays pivotal roles in eukaryotic DNA replication and repair. Polδ is conserved from yeast to humans, and mutations in human Polδ have been implicated in various cancers. Saccharomyces cerevisiae Polδ consists of catalytic Pol3 and the regulatory Pol31 and Pol32 subunits. Here, we present the near atomic resolution (3.2 Å) cryo-EM structure of yeast Polδ holoenzyme in the act of DNA synthesis. The structure reveals an unexpected arrangement in which the regulatory subunits (Pol31 and Pol32) lie next to the exonuclease domain of Pol3 but do not engage the DNA. The Pol3 C-terminal domain contains a 4Fe-4S cluster and emerges as the keystone of Polδ assembly. We also show that the catalytic and regulatory subunits rotate relative to each other and that this is an intrinsic feature of the Polδ architecture. Collectively, the structure provides a framework for understanding DNA transactions at the replication fork.

PMID:
31582849
DOI:
10.1038/s41594-019-0305-z

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