Cell 2012-12-01

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

Mrinal Srivastava, Mridula Nambiar, Sheetal Sharma, SubhasS Karki, G Goldsmith, Mahesh Hegde, Sujeet Kumar, Monica Pandey, RamK Singh, Pritha Ray, Renuka Natarajan, Madhura Kelkar, Abhijit De, Bibha Choudhary, SatheesC Raghavan

Index: Cell 151(7) , 1474-87, (2012)

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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.