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

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

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1
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.

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.

PMID:
23260137
DOI:
10.1016/j.cell.2012.11.054
[Indexed for MEDLINE]
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