Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

Vartak, Supriya V and Swarup, Hassan A and Gopalakrishnan, Vidya and Gopinatha, Vindya K and Ropars, Virginie and Nambiar, Mridula and John, Franklin and Kothanahally, Sharath Kumar S and Kumari, Rupa and Kumari, Nitu and Ray, Ujjayinee and Radha, Gudapureddy and Dinesh, Depina and Pandey, Monica and Ananda, Hanumappa and Karki, Subhas S and Srivastava, Mrinal and Charbonnier, Jean Baptiste and Choudhary, Bibha and Mantelingu, Kempegowda and Raghavan, Sathees C (2018) Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner. In: FEBS JOURNAL, 285 (21). pp. 3959-3976.

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Abstract

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, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 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 SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18H14N4OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18H12N4OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 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 SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-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 SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

Item Type:	Journal Article
Publication:	FEBS JOURNAL
Publisher:	WILEY
Additional Information:	Copy right for this article belong to WILEY
Keywords:	double-strand break; genome editing; homologous recombination; inhibitor of DNA repair; NHEJ
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	28 Nov 2018 15:13
Last Modified:	25 Aug 2022 08:17
URI:	https://eprints.iisc.ac.in/id/eprint/61177

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