High-fidelity DNA ligation enforces accurate Okazaki fragment maturation during DNA replication
| Autor: | Percy P. Tumbale, R. Scott Williams, Julian A. Rana, Mercedes E. Arana, Jessica S. Williams, Thomas A. Kunkel |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Replication
0301 basic medicine Saccharomyces cerevisiae Proteins DNA Ligases Flap Endonucleases DNA polymerase Science General Physics and Astronomy DNA-Directed DNA Polymerase Saccharomyces cerevisiae LIG1 DNA Mismatch Repair Article General Biochemistry Genetics and Molecular Biology DNA Ligase ATP 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Acetyltransferases DNA Fungal X-ray crystallography chemistry.chemical_classification DNA ligase Multidisciplinary biology Okazaki fragments Chemistry DNA replication Membrane Proteins DNA General Chemistry Cell biology Nuclear DNA 030104 developmental biology Mutagenesis Mutation biology.protein DNA mismatch repair 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | DNA ligase 1 (LIG1, Cdc9 in yeast) finalizes eukaryotic nuclear DNA replication by sealing Okazaki fragments using DNA end-joining reactions that strongly discriminate against incorrectly paired DNA substrates. Whether intrinsic ligation fidelity contributes to the accuracy of replication of the nuclear genome is unknown. Here, we show that an engineered low-fidelity LIG1Cdc9 variant confers a novel mutator phenotype in yeast typified by the accumulation of single base insertion mutations in homonucleotide runs. The rate at which these additions are generated increases upon concomitant inactivation of DNA mismatch repair, or by inactivation of the Fen1Rad27 Okazaki fragment maturation (OFM) nuclease. Biochemical and structural data establish that LIG1Cdc9 normally avoids erroneous ligation of DNA polymerase slippage products, and this protection is compromised by mutation of a LIG1Cdc9 high-fidelity metal binding site. Collectively, our data indicate that high-fidelity DNA ligation is required to prevent insertion mutations, and that this may be particularly critical following strand displacement synthesis during the completion of OFM. DNA ligase 1 (LIG1) finalizes eukaryotic nuclear DNA synthesis by sealing Okazaki fragments using DNA end-joining reactions. Here the authors, by studying an engineered low-fidelity LIG1, reveal that LIG1 is a highly accurate DNA ligase in vivo. |
| Databáze: | OpenAIRE |
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