Impaired nick recognition and ligation efficiency by LIG1 K845N variant linked to Huntington's disease.

ABSTRACT: DNA ligase 1 (LIG1) joins broken strand breaks and seals Okazaki fragments during DNA repair and replication. Huntington's disease (HD)-associated mutation in the LIG1 gene, K845N, is associated with delayed symptom onset and predicted to suppress CAG repeat expansion. Yet, how this mutation impacts faithful nick sealing and efficient DNA binding by LIG1 remains unknown. Here, using biochemical analyses, X-ray crystallography, and total internal reflection fluorescence (TIRF) microscopy, we characterized the LIG1 HD-associated K845N variant at biochemical, structural, and single-molecule levels. Our results showed significantly reduced ligation efficiency for nick substrates containing noncanonical mismatches and diminished mutagenic end-joining of damaged DNA, while LIG1 K845N vari

SUBMITTER: Ratcliffe J 

PROVIDER: S-EPMC12673853 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature