Human DNA ligase III has essential functions in nuclear and mitochondrial DNA
replication and repair and contains a PARP-like zinc finger (ZnF) that increases
DNA nick-joining and intermolecular DNA ligation. Yet, the bases for ligase III
specificity and structural variation among human ligases are not understood.
Here combined crystal structure and small angle x-ray scattering results reveal
dynamic switching between two nick-binding components of ligase III: the ZnF-DNA
binding domain (DBD) form a crescent-shaped surface used for DNA end recognition
which switches to a ring formed by the nucleotidyl transferase (NTase) -OB-fold
(OBD) domains for catalysis. Structural and mutational analyses indicate that
high flexibility and distinct DNA binding domain features in ligase III assist
both nick-sensing and the transition from nick-sensing by the ZnF to
nick-joining by the catalytic core. The collective results support a "jackknife
model" whereby the ZnF loads ligase III onto nicked DNA and conformational
changes deliver DNA into the active site. This work has implications for the
biological specificity of DNA ligases and functions of PARP-like zinc fingers.