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

Galanos, Panagiotis, Vougas, Konstantinos, Walter, David, Polyzos, Alexander, Maya-Mendoza, Apolinar, Haagensen, Emma J., Kokkalis, Antonis, Roumelioti, Fani-Marlen, Gagos, Sarantis, Tzetis, Maria, Canovas, Begoña, Igea, Ana, Ahuja, Akshay K., Zellweger, Ralph, Havaki, Sofia, Kanavakis, Emanuel, Kletsas, Dimitris, Roninson, Igor B., Garbis, Spiros D., Lopes, Massimo, Nebreda, Angel, Thanos, Dimitris, Blow, J. Julian ORCID: https://orcid.org/0000-0002-9524-5849, Townsend, Paul, Sørensen, Claus Storgaard, Bartek, Jiri and Gorgoulis, Vassilis G. (2016) Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nature Cell Biology, 18 (7). pp. 777-789. ISSN 1465-7392

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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.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:
Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 14:30
Last Modified:	23 Jul 2024 02:22
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95456
DOI:	10.1038/ncb3378

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