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. 2012 Mar 13;4(6):515–527. doi: 10.1002/emmm.201200229

Figure 6. Model for the cellular effects of PARP inhibitors in MCL cells.

Figure 6

Olaparib prevents PARP-1 mediated repair of endogenous DNA SSBs generated by reactive oxygen species (ROS) and intermediates of base excision repair (BER), as well as one-ended DNA DSBs produced when replication forks collapse. In ATM-proficient cells, these DSBs activate ATM inducing transient cell cycle checkpoints and repair of the breaks by HR. In ATM-deficient cells, olaparib activates DNA-PK, and possibly ATR, which phosphorylate and stabilize p53 resulting in upregulation of cell cycle checkpoint genes GADD45α and p21, providing a survival advantage over cells with mutant p53. ATM-deficient cells initiate NHEJ to attempt to repair one-ended DNA DSBs regardless of p53 status, leading to cell death, via p53-independent apoptosis.