Two-tiered enforcement of high-fidelity DNA ligation.
Nat Commun
; 10(1): 5431, 2019 11 28.
Article
em En
| MEDLINE
| ID: mdl-31780661
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Proteínas Nucleares
/
Proteínas de Ligação a DNA
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DNA Ligase Dependente de ATP
/
Magnésio
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article