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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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)
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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
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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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