| First Author | Lin RK | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 10 | Pages | 7182-92 |
| PubMed ID | 23344961 | Mgi Jnum | J:196888 |
| Mgi Id | MGI:5490165 | Doi | 10.1074/jbc.M112.415471 |
| Citation | Lin RK, et al. (2013) Topoisomerase IIbeta deficiency enhances camptothecin-induced apoptosis. J Biol Chem 288(10):7182-92 |
| abstractText | Camptothecin (CPT), a topoisomerase (Top) I-targeting drug that stabilizes Top1-DNA covalent adducts, can induce S-phase-specific cytotoxicity due to the arrest of progressing replication forks. However, CPT-induced non-S-phase cytotoxicity is less well characterized. In this study, we have identified topoisomerase IIbeta (Top2beta) as a specific determinant for CPT sensitivity, but not for many other cytotoxic agents, in non-S-phase cells. First, quiescent mouse embryonic fibroblasts (MEFs) lacking Top2beta were shown to be hypersensitive to CPT with prominent induction of apoptosis. Second, ICRF-187, a Top2 catalytic inhibitor known to deplete Top2beta, specifically sensitized MEFs to CPT. To explore the molecular basis for CPT hypersensitivity in Top2beta-deficient cells, we found that upon CPT exposure, the RNA polymerase II large subunit (RNAP LS) became progressively depleted, followed by recovery to nearly the original level in wild-type MEFs, whereas RNAP LS remained depleted without recovery in Top2beta-deficient cells. Concomitant with the reduction of the RNAP LS level, the p53 protein level was greatly induced. Interestingly, RNAP LS depletion has been well documented to lead to p53-dependent apoptosis. Altogether, our findings support a model in which Top2beta deficiency promotes CPT-induced apoptosis in quiescent non-S-phase cells, possibly due to RNAP LS depletion and p53 accumulation. |
