Structure and mechanism of B-family DNA polymerase ζ specialized for translesion DNA synthesis

Radhika Malik, Mykhailo Kopylov, Yacob Gomez-Llorente, Rinku Jain, Robert E. Johnson, Louise Prakash, Satya Prakash, Iban Ubarretxena-Belandia, Aneel K. Aggarwal

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

DNA polymerase ζ (Polζ) belongs to the same B-family as high-fidelity replicative polymerases, yet is specialized for the extension reaction in translesion DNA synthesis (TLS). Despite its importance in TLS, the structure of Polζ is unknown. We present cryo-EM structures of the Saccharomycescerevisiae Polζ holoenzyme in the act of DNA synthesis (3.1 Å) and without DNA (4.1 Å). Polζ displays a pentameric ring-like architecture, with catalytic Rev3, accessory Pol31‚ Pol32 and two Rev7 subunits forming an uninterrupted daisy chain of protein–protein interactions. We also uncover the features that impose high fidelity during the nucleotide-incorporation step and those that accommodate mismatches and lesions during the extension reaction. Collectively, we decrypt the molecular underpinnings of Polζ’s role in TLS and provide a framework for new cancer therapeutics.

Original languageEnglish (US)
Pages (from-to)913-924
Number of pages12
JournalNature Structural and Molecular Biology
Volume27
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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