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

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.
Authors	Mrinal Srivastava, 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
Journal	Cell (Cell) Vol. 151 Issue 7 Pg. 1474-87 (Dec 21 2012) ISSN: 1097-4172 [Electronic] United States
PMID	23260137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2012 Elsevier Inc. All rights reserved.
Chemical References	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
Topics	Amino Acid Sequence Animals Cell Line, Tumor DNA Breaks, Double-Stranded DNA End-Joining Repair (drug effects) DNA Ligase ATP DNA Ligases (antagonists & inhibitors, chemistry, genetics) Disease Models, Animal Drug Design Drug Resistance, Neoplasm Humans Lymphocytes (drug effects) Lymphoma (drug therapy, pathology) Male Mice Mice, Inbred BALB C Mice, Nude Models, Molecular Molecular Sequence Data Neoplasms (drug therapy, pathology) Protein Structure, Tertiary Pyrimidines (chemical synthesis, chemistry, therapeutic use) Radiation Tolerance Rats Schiff Bases (chemical synthesis, chemistry, therapeutic use) Sequence Alignment

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