The O'Brien lab publishes a research article in PNAS

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

A research team led by Dr. Patrick O'Brien (U-M Biological Chemistry), Dr. Vanessa Wheeler (MGH, Harvard, Broad Institute) and Dr. Ihn Sik Seong (MGH, Harvard) investigated a missense variant in DNA Ligase 1 (K845N) that is associated with a profound delay in the onset of Huntington’s disease (HD). Using in vitro ligase assays, human cell-based studies, and a mouse model of HD, they discovered that K845N ligase enhances substrate discrimination against mismatched substrates, thus increasing DNA repair fidelity, conferring protection against oxidative stress and slowing somatic expansion of the HD CAG repeat. Their results provide a mechanistic foundation for considering DNA ligase fidelity as a therapeutic target in HD and potentially in other trinucleotide repeat disorders. Biological Chemistry PhD student David Beier shares first authorship of the paper with Eunhye Lee from the Seong lab and Wonju Kim from the Wheeler lab.

Article in PNAS

protein domain structure of human DNA ligase I
K845 makes interdomain contacts between the OBD (yellow) and AdD (green) in wild-type LIG1 (PDB 6p0c).

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In This Story
Patrick O'Brien

Patrick O'Brien

Professor

David beier

David Beier

PhD Student, Biological Chemistry | Patrick O'Brien Lab

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