Structural Basis of DNA Ligase IV-Artemis Interaction in Nonhomologous End-Joining

SummaryDNA ligase IV (LigIV) and Artemis are central components of the nonhomologous end-joining (NHEJ) machinery that is required for V(D)J recombination and the maintenance of genomic integrity in mammalian cells. We report here crystal structures of the LigIV DNA binding domain (DBD) in both its apo form and in complex with a peptide derived from the Artemis C-terminal region. We show that LigIV interacts with Artemis through an extended hydrophobic surface. In particular, we find that the helix α2 in LigIV-DBD is longer than in other mammalian ligases and presents residues that specifically interact with the Artemis peptide, which adopts a partially helical conformation on binding. Mutations of key residues on the LigIV-DBD hydrophobic surface abolish the interaction. Together, our results provide structural insights into the specificity of the LigIV-Artemis interaction and how the enzymatic activities of the two proteins may be coordinated during NHEJ.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Crystal structure of the Ligase-IV-Artemis complex
► Ligase IV DNA binding domain contains a unique hydrophobic cavity
► The structure shows why only Ligase IV can recruit Artemis
► Insights into how activities of Ligase IV and Artemis may be coordinated in NHEJ