DNA polymerase δ proofreads errors made by DNA polymerase ε
| Autor: | Chelsea R. Bulock, Xuanxuan Xing, Polina V. Shcherbakova |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
DNA Replication
Mutation rate Saccharomyces cerevisiae Proteins Direct evidence DNA polymerase Saccharomyces cerevisiae medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Mutation Rate Genetics medicine DNA Polymerase III 030304 developmental biology Physics 0303 health sciences Mutation Multidisciplinary biology Mutagenesis DNA replication extrinsic proofreading DNA polymerase δ Biological Sciences DNA polymerase ε Cell biology enzymes and coenzymes (carbohydrates) 030220 oncology & carcinogenesis Mutagenesis Site-Directed biology.protein Proofreading |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Polδ and Polε are the two major replicative polymerases in eukaryotes, but their precise roles at the replication fork remain a subject of debate. A bulk of data supports a model where Polε and Polδ synthesize leading and lagging DNA strands, respectively. However, this model has been difficult to reconcile with the fact that mutations in Polδ have much stronger consequences for genome stability than equivalent mutations in Polε. We provide direct evidence for a long-entertained idea that Polδ can proofread errors made by Polε in addition to its own errors, thus, making a more prominent contribution to mutation avoidance. This paper provides an essential advance in the understanding of the mechanism of eukaryotic DNA replication. During eukaryotic replication, DNA polymerases ε (Polε) and δ (Polδ) synthesize the leading and lagging strands, respectively. In a long-known contradiction to this model, defects in the fidelity of Polε have a much weaker impact on mutagenesis than analogous Polδ defects. It has been previously proposed that Polδ contributes more to mutation avoidance because it proofreads mismatches created by Polε in addition to its own errors. However, direct evidence for this model was missing. We show that, in yeast, the mutation rate increases synergistically when a Polε nucleotide selectivity defect is combined with a Polδ proofreading defect, demonstrating extrinsic proofreading of Polε errors by Polδ. In contrast, combining Polδ nucleotide selectivity and Polε proofreading defects produces no synergy, indicating that Polε cannot correct errors made by Polδ. We further show that Polδ can remove errors made by exonuclease-deficient Polε in vitro. These findings illustrate the complexity of the one-strand–one-polymerase model where synthesis appears to be largely divided, but Polδ proofreading operates on both strands. |
| Databáze: | OpenAIRE |
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