An Inhibitor of Nonhomologous End-Joining Abrogates Double-Strand Break Repair and Impedes Cancer Progression

SummaryDNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (148 K)Download as PowerPoint slideHighlights► SCR7, a Ligase IV inhibitor, blocks NHEJ in vitro and in vivo ► Inhibitor interferes with DNA binding domain association with double-strand breaks ► SCR7 impedes progression of tumors in mouse models, leading to enhanced lifespan ► Persistent breaks potentiate the effects of radio- and chemotherapy