Autocyclized and oxidized forms of SCR 7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

• Published in: The FEBS journal Vol. 285; no. 21; pp. 3959 - 3976
• Main Authors: Vartak, Supriya V., Swarup, Hassan A., Gopalakrishnan, Vidya, Gopinatha, Vindya K., Ropars, Virginie, Nambiar, Mridula, John, Franklin, Kothanahally, Sharath Kumar S., Kumari, Rupa, Kumari, Nitu, Ray, Ujjayinee, Radha, Gudapureddy, Dinesh, Depina, Pandey, Monica, Ananda, Hanumappa, Karki, Subhas S., Srivastava, Mrinal, Charbonnier, Jean Baptiste, Choudhary, Bibha, Mantelingu, Kempegowda, Raghavan, Sathees C.
• Format: Journal Article
• Language: English
• Published: 01-11-2018
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14661

Nonhomologous DNA end joining ( NHEJ ) is the major DNA double‐strand break ( DSB ) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR 7, which can inhibit NHEJ in a Ligase IV ‐dependent manner. Administration of SCR 7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR 7, which is unstable, can be autocyclized into a stable form. Both parental SCR 7 and cyclized SCR 7 possess the same molecular weight (334.09) and molecular formula (C 18 H 14 N 4 OS ), whereas its oxidized form, SCR 7‐pyrazine, possesses a different molecular formula (C 18 H 12 N 4 OS ), molecular weight (332.07), and structure. While cyclized form of SCR 7 showed robust inhibition of NHEJ in vitro , both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR 7 inhibited DNA end joining catalyzed by Ligase IV , whereas their impact was minimal on Ligase III , Ligase I, and T4 DNA Ligase‐mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR 7‐cyclized. Both forms blocked NHEJ in a Ligase IV ‐dependent manner leading to the accumulation of DSB s within the cells. Although cytotoxicity due to SCR 7‐cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV ‐null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR 7 can inhibit NHEJ in a Ligase IV ‐dependent manner, although SCR 7‐pyrazine is less specific to Ligase IV inside the cell.