title: 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.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Srivastava
authors.forename: Mridula
authors.initials: M
authors.lastname: Nambiar
authors.forename: Sheetal
authors.initials: S
authors.lastname: Sharma
authors.forename: Subhas S
authors.initials: SS
authors.lastname: Karki
authors.forename: G
authors.initials: G
authors.lastname: Goldsmith
authors.forename: Mahesh
authors.initials: M
authors.lastname: Hegde
authors.forename: Sujeet
authors.initials: S
authors.lastname: Kumar
authors.forename: Monica
authors.initials: M
authors.lastname: Pandey
authors.forename: Ram K
authors.initials: RK
authors.lastname: Singh
authors.forename: Pritha
authors.initials: P
authors.lastname: Ray
authors.forename: Renuka
authors.initials: R
authors.lastname: Natarajan
authors.forename: Madhura
authors.initials: M
authors.lastname: Kelkar
authors.forename: Abhijit
authors.initials: A
authors.lastname: De
authors.forename: Bibha
authors.initials: B
authors.lastname: Choudhary
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000187:drug effects*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D004195:Disease Models, Animal; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011836:Radiation Tolerance; D051381:Rats; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D016415:Sequence Alignment
chemical_list: C578537:5,6-bis(benzylideneamino)-2-mercaptopyrimidin-4-ol; C000607892:LIG1 protein, human; C000607893:LIG4 protein, human; C000607895:Lig1 protein, rat; D011743:Pyrimidines; D012545:Schiff Bases; D011088:DNA Ligases; D000072481:DNA Ligase ATP