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

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.
Mrinal Srivastava 1,  Mridula Nambiar,  Sheetal Sharma,  Subhas S Karki,  G Goldsmith,  Mahesh Hegde,  Sujeet Kumar,  Monica Pandey,  Ram K Singh,  Pritha Ray,  Renuka Natarajan,  Madhura Kelkar,  Abhijit De,  Bibha Choudhary,  Sathees C Raghavan
Affiliations

Affiliation

  • 1 Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
PMID: 23260137 DOI: 10.1016/j.cell.2012.11.054
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.

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