Huntington’s disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Eunhye Lee
Wonju Kim
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
David H. Beier
Yejin Lee
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Marina Kovalenko
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Faaiza Saif
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Esaria Oliver
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Bhairavi Srinageshwar
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Ryan Murtha
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Marissa A. Andrew
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Andrew Jiang
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Tammy Gillis
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Brigitte Demelo
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Jayla Ruliera
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Diane Lucente
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Seung Kwak
CHDI Management Inc.
Ramee Lee
CHDI Management Inc.
Ricardo Mouro Pinto
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Marcy E. MacDonald
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
James F. Gusella
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital
Patrick J. O’Brien
Vanessa C. Wheeler
Ihn Sik Seong