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

Cell. 2012 Dec 21;151(7):1474-87. doi: 10.1016/j.cell.2012.11.054.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair / drug effects*
  • DNA Ligase ATP
  • DNA Ligases / antagonists & inhibitors*
  • DNA Ligases / chemistry
  • DNA Ligases / genetics
  • Disease Models, Animal
  • Drug Design
  • Drug Resistance, Neoplasm
  • Humans
  • Lymphocytes / drug effects
  • Lymphoma / drug therapy
  • Lymphoma / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / drug therapy*
  • Neoplasms / pathology*
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / therapeutic use*
  • Radiation Tolerance
  • Rats
  • Schiff Bases / chemical synthesis
  • Schiff Bases / chemistry
  • Schiff Bases / therapeutic use*
  • Sequence Alignment


  • 5,6-bis(benzylideneamino)-2-mercaptopyrimidin-4-ol
  • LIG1 protein, human
  • LIG4 protein, human
  • Lig1 protein, rat
  • Pyrimidines
  • Schiff Bases
  • DNA Ligases
  • DNA Ligase ATP