Two-tiered enforcement of high-fidelity DNA ligation

Percy P. Tumbale, Thomas J. Jurkiw, Matthew J. Schellenberg, Amanda A. Riccio, Patrick J O’Brien () and R. Scott Williams ()
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Percy P. Tumbale: US National Institutes of Health, Department of Health and Human Services
Thomas J. Jurkiw: University of Michigan
Matthew J. Schellenberg: US National Institutes of Health, Department of Health and Human Services
Amanda A. Riccio: US National Institutes of Health, Department of Health and Human Services
Patrick J O’Brien: University of Michigan
R. Scott Williams: US National Institutes of Health, Department of Health and Human Services

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract DNA ligases catalyze the joining of DNA strands to complete DNA replication, recombination and repair transactions. To protect the integrity of the genome, DNA ligase 1 (LIG1) discriminates against DNA junctions harboring mutagenic 3′-DNA mismatches or oxidative DNA damage, but how such high-fidelity ligation is enforced is unknown. Here, X-ray structures and kinetic analyses of LIG1 complexes with undamaged and oxidatively damaged DNA unveil that LIG1 employs Mg2+-reinforced DNA binding to validate DNA base pairing during the adenylyl transfer and nick-sealing ligation reaction steps. Our results support a model whereby LIG1 fidelity is governed by a high-fidelity (HiFi) interface between LIG1, Mg2+, and the DNA substrate that tunes the enzyme to release pro-mutagenic DNA nicks. In a second tier of protection, LIG1 activity is surveilled by Aprataxin (APTX), which suppresses mutagenic and abortive ligation at sites of oxidative DNA damage.

Date: 2019
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DOI: 10.1038/s41467-019-13478-7

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