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Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
Open accessAbstract
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.
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“Similar characteristics were seen in CIP1 -overexpressing TP53 -null cultured cancer cells, which entered a transient senescent state but quickly escaped with enhanced cancer stem cell properties and an aggressive phenotype 190 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [190]
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In the citing paper
“Although the senescence cell-cycle arrest is generally irreversible, cell-cycle re-entry can occur under certain circumstances, particularly in tumor cells (Galanos et al., 2016; Milanovic et al., 2018; Patel et al., 2016; Saleh et al., 2019) (Figure 2).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Galanos et al., 2016
In the citing paper
“Because p21 overexpression caused the downregulation of RAD51 [71], DSBs were processed by error-prone pathways, including RAD52-dependent break-induced replication (BIR) and single-strand annealing (SSA) [75], and possibly nonhomologous end-joining [71].”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“Because both rereplication and error-prone DSB repair fuel genomic instability, these observations indicate a pro-oncogenic role of p21, at least in p53-negative cancer [71,75].”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“Moreover, replication-fork progression was asymmetric and slow, and DSBs accumulated in a manner that depended on CDT1 and CDC6 overexpression.”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“p21-overexpressing cells acquired the capacity to rereplicate.”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“The dependency on PCNA was confirmed using a p21 mutant with a disrupted PIP box (Q144A, M147A, and F150A), which did not cause CDT1 and CDC6 upregulation [71].”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“By exploring markers of active replication (KI67) and p21 levels in human tumors, unexpected colocalization of p21 and ki67 was observed in approximately 5% to 7% of cells within p53-deficient tumors [71].”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [71]
In the citing paper
“Although the cell cycle arrest in cellular senescence is believed to be irreversible, studies have recently shown that senescent cells can under certain circumstances re-enter the cell cycle such as in tumor cells (Galanos et al., 2016; Patel et al., 2016; Milanovic et al., 2018; Saleh et al., 2019) or be reprogrammed into induced pluripotent stem cells (Banito and Gil, 2010; Lapasset et al., 2011”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Galanos et al., 2016
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Metadata
- Authors
- 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., Lopes, M., Nebreda, A., Thanos, D., Blow, J. J., Townsend, P., Sørensen, C. S., Bartek, J., & Gorgoulis, V. G.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- University of Copenhagen (DK)
- University of Dundee (GB)
- Institute for Research in Biomedicine (ES)
- University of Zurich (CH)
- National Centre of Scientific Research "Demokritos" (GR)
- University of South Carolina (US)
- University of Southampton (GB)
- Manchester Academic Health Science Centre (GB)
- Corresponding author
- Gorgoulis, Vassilis G.
- ORCID
- Galanos, Panagiotis
- Vougas, Konstantinos
- Walter, David
- Polyzos, Alexander
- Haagensen, Emma J.
- Kokkalis, Antonis
- Roumelioti, Fani-Marlen
- Gagos, Sarantis
- Tzetis, Maria
- Igea, Ana
- Ahuja, Akshay K.
- Kletsas, Dimitris
- Roninson, Igor B.
- Garbis, Spiros D.
- Lopes, Massimo
- Thanos, Dimitris
- Blow, J. Julian
- Townsend, Paul
- Sørensen, Claus Storgaard
- Gorgoulis, Vassilis G.
- Venue
- Nature Cell Biology
- Published
- 2016-06-20
- Volume
- 18
- Issue
- 7
- Pages
- 777-789
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6535144
- OpenAlex
- W2470774921
- Cited by
- 308
- References
- 90
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 35 · 2023: 29 · 2022: 26 · 2021: 40 · 2020: 22 · 2019: 37 · 2018: 25 · 2017: 27 · 2016: 20
- FWCI
- 19.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by-nc)
- Funders
- Wellcome Trust (096598, 096598/Z/11/Z, 097945/C/11/Z)
- European Commission (284460)
- General Secretariat for Research and Technology
- Lundbeckfonden (R93-2011-8990)
- Novo Nordisk Fonden (NNF15OC0016584, NNF12OC0002290)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- p21, genomic instability, replication licensing, replication stress, senescence, chemoresistance, tumor aggressiveness, cell proliferation
- MeSH terms
- Cells, Cultured, DNA Replication, Humans, Neoplasms, Tumor Suppressor Protein p53, Cyclins, Genomic Instability, Cyclin-Dependent Kinase Inhibitor p21
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