High fidelity DNA ligation prevents single base insertions in the yeast genome

Jessica S. Williams, Scott. A. Lujan, Mercedes E. Arana, Adam B. Burkholder, Percy P. Tumbale, R. Scott Williams and Thomas A. Kunkel ()
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Jessica S. Williams: 111 TW Alexander Drive
Scott. A. Lujan: 111 TW Alexander Drive
Mercedes E. Arana: 111 TW Alexander Drive
Adam B. Burkholder: 111 TW Alexander Drive
Percy P. Tumbale: 111 TW Alexander Drive
R. Scott Williams: 111 TW Alexander Drive
Thomas A. Kunkel: 111 TW Alexander Drive

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Finalization of eukaryotic nuclear DNA replication relies on DNA ligase 1 (LIG1) to seal DNA nicks generated during Okazaki Fragment Maturation (OFM). Using a mutational reporter in Saccharomyces cerevisiae, we previously showed that mutation of the high-fidelity magnesium binding site of LIG1Cdc9 strongly increases the rate of single-base insertions. Here we show that this rate is increased across the nuclear genome, that it is synergistically increased by concomitant loss of DNA mismatch repair (MMR), and that the additions occur in highly specific sequence contexts. These discoveries are all consistent with incorporation of an extra base into the nascent lagging DNA strand that can be corrected by MMR following mutagenic ligation by the Cdc9-EEAA variant. There is a strong preference for insertion of either dGTP or dTTP into 3–5 base pair mononucleotide sequences with stringent flanking nucleotide requirements. The results reveal unique LIG1Cdc9-dependent mutational motifs where high fidelity DNA ligation of a subset of OFs is critical for preventing mutagenesis across the genome.

Date: 2024
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DOI: 10.1038/s41467-024-53063-1

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