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 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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line, Tumor
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DNA Breaks, Double-Stranded*
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DNA End-Joining Repair / drug effects*
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DNA Ligase ATP
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DNA Ligases / antagonists & inhibitors*
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DNA Ligases / chemistry
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DNA Ligases / genetics
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Disease Models, Animal
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Drug Design
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Drug Resistance, Neoplasm
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Humans
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Lymphocytes / drug effects
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Lymphoma / drug therapy
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Lymphoma / pathology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Models, Molecular
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Molecular Sequence Data
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Neoplasms / drug therapy*
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Neoplasms / pathology*
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Protein Structure, Tertiary
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / therapeutic use*
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Radiation Tolerance
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Rats
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Schiff Bases / chemical synthesis
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Schiff Bases / chemistry
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Schiff Bases / therapeutic use*
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Sequence Alignment
Substances
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5,6-bis(benzylideneamino)-2-mercaptopyrimidin-4-ol
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LIG1 protein, human
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LIG4 protein, human
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Lig1 protein, rat
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Pyrimidines
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Schiff Bases
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DNA Ligases
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DNA Ligase ATP