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Two-tiered enforcement of high-fidelity DNA ligation.

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.

SUBMITTER: Tumbale PP

PROVIDER: S-EPMC6882888 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Two-tiered enforcement of high-fidelity DNA ligation.

Tumbale Percy P PP Jurkiw Thomas J TJ Schellenberg Matthew J MJ Riccio Amanda A AA O'Brien Patrick J PJ Williams R Scott RS

Nature communications 20191128 1

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 Mg<sup>2+</sup>-reinforced DNA bind ...[more]

PMID: 31780661

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