An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression

Abstract

DNA 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 co-administered 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.