14-3-3{sigma} Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

14-3-3 has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3 contributes to these resistances via inhibiting apoptosis and arresting cells in G₂–M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3 causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G₂–M phase following DNA-damaging treatments. We showed that 14-3-3 contributed to ionizing radiation (IR) resistance by arresting cancer cells in G₂–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G₂–M arrest following IR was due to 14-3-3–induced Chk2 expression.

Implications: These findings reveal an important molecular basis of 14-3-3 function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers. Mol Cancer Res; 15(4); 418–28. ©2017 AACR.

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