LIG1 syndrome mutations remodel a cooperative network of ligand binding interactions to compromise ligation efficiency.

ABSTRACT: Human DNA ligase I (LIG1) is the main replicative ligase and it also seals DNA breaks to complete DNA repair and recombination pathways. Immune compromised patients harbor hypomorphic LIG1 alleles encoding substitutions of conserved arginine residues, R771W and R641L, that compromise LIG1 activity through poorly defined mechanisms. To understand the molecular basis of LIG1 syndrome mutations, we determined high resolution X-ray structures and performed systematic biochemical characterization of LIG1 mutants using steady-state and pre-steady state kinetic approaches. Our results unveil a cooperative network of plastic DNA-LIG1 interactions that connect DNA substrate engagement with productive binding of Mg2+ cofactors for catalysis. LIG1 syndrome mutations destabilize this network, compromi

SUBMITTER: Jurkiw TJ 

PROVIDER: S-EPMC7897520 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature