The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ

Denis A. Kiktev, Margaret Dominska, Tony Zhang, Joseph Dahl, Elena I. Stepchenkova, Piotr Mieczkowski, Peter M. Burgers, Scott Lujan, Adam Burkholder, Thomas A. Kunkel, Thomas D. Petes

Research output: Contribution to journalArticlepeer-review

Abstract

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants of POL2 (Pol Ïμ) do not elevate deletions. Further support for the conclusion that met18 strains result in impaired DNA synthesis by Pol δare the observations that Pol δisolated from met18 strains has less bound iron and is less processive in vitro than the wild-type holoenzyme.

Original languageEnglish
Pages (from-to)5623-5636
Number of pages14
JournalNucleic acids research
Volume49
Issue number10
DOIs
StatePublished - Jun 4 2021

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