Huntington’s disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion

TL;DR

A DNA Ligase 1 variant delays Huntington’s disease onset by improving DNA repair accuracy and reducing harmful genetic changes.

Contribution

The study reveals how a specific LIG1 variant reduces CAG repeat expansion and offers a new therapeutic target for HD.

Findings

The K845N variant increases DNA ligase fidelity toward mismatched substrates.

The variant protects against oxidative stress and slows somatic CAG repeat expansion in HD mice.

Altered LIG1 function may delay HD onset by reducing genomic damage in the brain.

Abstract

We analyzed a missense variant in DNA Ligase 1 (K845N) that is associated with a profound delay in the onset of Huntington’s disease (HD). We find that K845N enhances substrate discrimination toward mismatched substrates, thus increasing repair fidelity, conferring protection against oxidative stress and slows somatic expansion of the HD CAG repeat. Our observations provide insight into underlying mechanisms of disease modification and suggest avenues that can be harnessed for disease-modifying therapeutic intervention.

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by inheriting an expanded CAG repeat tract in the huntingtin gene (HTT) that further expands in somatic cells over an individual’s lifetime. Genome-wide association studies have provided critical insight into factors that modify the course of disease. These include DNA repair genes that alter the rate of somatic expansion and other genes that do not appear to directly influence this process. One modifier gene is DNA ligase 1 (LIG1), in which a variant specifying a lysine to asparagine substitution (K845N) is associated with a profound (7 to 8 y) delay in the onset of motor signs. Here, we have taken a multifaceted approach to gain insight into the protective nature of this variant in HD. We demonstrate using in vitro ligase assays and enzyme kinetics that K845N enhances discrimination toward mismatched substrates and increases repair fidelity. Consistent with increased ligation fidelity, K845N confers protection against oxidative stress in cell-based assays. Finally, we demonstrate that the mouse LIG1 K843N orthologue suppresses somatic CAG expansion in HD knock-in mice. Overall, our data provide evidence that altered LIG1 function due to the K845N substitution may contribute to HD clinical delay by slowing somatic expansion in the brain and protecting the genome globally against damage. Significantly, our results provide a mechanistic foundation for considering DNA ligase fidelity as a therapeutic target in HD and potentially in other trinucleotide repeat disorders.

Figures