Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

摘要: The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through mechanism has so far remained obscure. We report subset atypical cancerous cells strongly expressing showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation selectively more aggressive tumour cells. Multifaceted phenotypic genomic analyses p21-inducible, p53-null, near-normal cellular models after an initial senescence-like phase, subpopulation p21-expressing proliferating emerged, featuring increased instability, aggressiveness chemoresistance. Mechanistically, sustained accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing replication stress. Collectively, our data reveal tumour-promoting ability deregulation DNA machinery-an unorthodox role considered cancer treatment, since responds various stimuli including some chemotherapy drugs.