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

Nature structural & molecular biology 2020 Oct

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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 Saccharomyces cerevisiae 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.

Citation

Radhika Malik, Mykhailo Kopylov, Yacob Gomez-Llorente, Rinku Jain, Robert E Johnson, Louise Prakash, Satya Prakash, Iban Ubarretxena-Belandia, Aneel K Aggarwal. Structure and mechanism of B-family DNA polymerase ζ specialized for translesion DNA synthesis. Nature structural & molecular biology. 2020 Oct;27(10):913-924