Proteasome inhibitor induced ROS generation and cell cycle arrest. Proteasome inhibitors increase the endogenous level of reactive oxygen species which causes DNA damage by inducing double strand breaks in intact DNA. PIs treatment leads to accumulation of p53 which senses this DNA damage. p53 reactivation upregulates p21 expression, a CDK inhibitor. p21 binds and inactivates Cyclin B and CDK2 and causes G2/M cell cycle arrest in response to PIs.