Protracted p53-independent stimulation of p21 fuels genomic instability by deregulating the replication licensing machinery

The cyclin-dependent kinase inhibitor p21 is the prototype downstream effector of the tumor suppressor protein p53. Yet, evidence from human cancer and mice models, imply that p21, under certain conditions, can exercise oncogenic activity. The mechanism behind this behavior is still obscure. Within this context we unexpectedly noticed, predominantly in p53 mutant human cancers, that a subset of highly atypical cancerous cells expressing strongly p21 demonstrated also signs of proliferation. This finding suggests either tolerance to high p21 levels or that p21 per se guided a selective process that led to more aggressive off-springs. To address the latter scenario we employed p21inducible p53-null cellular models and monitored them over a prolonged time period, using high-throughput screening means. After an initial phase characterized by stalled growth, mainly due to senescence, a subpopulation of p21 cells emerged, demonstrating increased genomic instability, aggressiveness and chemo-resistance. At the mechanistic level unremitted p21 production “saturates” the CRL4 and SCF ubiquitin ligase complexes reducing the turn-over of the replication licensing machinery. Deregulation of replication licensing triggered replication stress fuelling genomic instability. Conceptually, the above notion should be considered when anti-tumor strategies are designed, since p21 responds also to p53independent signals, including various chemotherapeutic compounds.