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

作者：Supriya V., Vartak; Hassan A., Swarup; Vidya, Gopalakrishnan; Vindya K., Gopinatha; Virginie, Ropars; Mridula, Nambiar; Franklin, John; Sharath Kumar S., Kothanahally; Rupa, Kumari; Nitu, Kumari; Ujjayinee, Ray; Gudapureddy, Radha; Depina, Dinesh; Monica, Pandey; Hanumappa, Ananda; Subhas S., Karki; Mrinal, Srivastava; Jean Baptiste, Charbonnier; Bibha, Choudhary; Kempegowda, Mantelingu; Sathees C., Raghavan

来源：FEBS Journal, 2018, 285(21): 3959-3976.

DOI：10.1111/febs.14661

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

• 出版日期2018-11
• 单位中国地震局