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Nuclear PTEN interferes with binding of Ku70 at double-strand breaks through post-translational poly(ADP-ribosyl)ation

PTEN is a tumor suppressor gene characterized as a phosphatase that antagonizes the phosphatidylinositol 3-kinase signaling pathway in the cytoplasm. Nuclear PTEN plays roles in chromosomal stability, in which the double-strand breaks (DSB) repair mediated by homologous recombination (HR) and non-homologous end joining (NHEJ) is critical. Herein, the role of nuclear PTEN in DSB repair and the underlying molecular mechanism was investigated in this study. Using human breast cancer BT549 and MDA-MB-231 cell lines, we reveal a specific feature of PTEN that controls poly(ADP-ribosyl)ation of Ku70 and interferes with binding of Ku70 at DSB. Plasmid-based end joining and reporter assays showed that nuclear PTEN restrained NHEJ efficacy. Electrophoretic mobility shift assays showed that nuclear PTEN impaired Ku70 complex binding to DSB by 3-fold. Co-immunoprecipitation assay showed PTEN regulated poly(ADP-ribosyl)ation of Ku70 instead of directly interacting with Ku70, while PTEN promoted the poly(ADP-ribosyl)ation of PARP1 and induced the degradation of PARP1 in PTEN-WT cells exposed to DSB agents. Of note, the role of PTEN in DSB repair mostly depends on its nuclear localization rather than its phosphatase activity. As a result, the absence of nuclear PTEN rather than phosphatase-negative PTEN confers cell hypersensitivity to anti-tumor DNA damage drugs. This finding contributes to understanding the effect of PTEN in repair of DSB and using defined anti-tumor DSB drugs to treat tumor cells with aberrant PTEN.

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