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

Panagiotis Galanos, Konstantinos Vougas, David Walter, Alexander Polyzos, Apolinar Maya-Mendoza, Emma J. Haagensen, Antonis Kokkalis, Fani-Marlen Roumelioti, Sarantis Gagos, Maria Tzetis, Begoña Canovas, Ana Igea, Akshay K. Ahuja, Ralph Zellweger, Sofia Havaki, Emanuel Kanavakis, Dimitris Kletsas, Igor B. Roninson, Spiros D. Garbis, Massimo LopesAngel Nebreda, Dimitris Thanos, J. Julian Blow, Paul Townsend, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G. Gorgoulis

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Abstract

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

Original languageEnglish
Pages (from-to)777-789
Number of pages13
JournalNature Cell Biology
Volume18
Issue number7
Early online date20 Jun 2016
DOIs
Publication statusPublished - Jul 2016

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Galanos, P., Vougas, K., Walter, D., Polyzos, A., Maya-Mendoza, A., Haagensen, E. J., Kokkalis, A., Roumelioti, F-M., Gagos, S., Tzetis, M., Canovas, B., Igea, A., Ahuja, A. K., Zellweger, R., Havaki, S., Kanavakis, E., Kletsas, D., Roninson, I. B., Garbis, S. D., ... Gorgoulis, V. G. (2016). Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nature Cell Biology, 18(7), 777-789. https://doi.org/10.1038/ncb3378