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 Lopes; Angel Nebreda; Dimitris Thanos; J Julian Blow; Paul Townsend; Claus Storgaard Sørensen; Jiri Bartek; Vassilis G Gorgoulis

doi:10.1038/ncb3378

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

129 Citations (Scopus)

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 language	English
Journal	Nature Cell Biology
Volume	18
Issue number	7
Pages (from-to)	777-89
Number of pages	13
ISSN	1465-7392
DOIs	https://doi.org/10.1038/ncb3378
Publication status	Published - 28 Jun 2016

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Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncb3378

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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), 777-89. https://doi.org/10.1038/ncb3378

Galanos, P, Vougas, K, Walter, D, Polyzos, A, Maya-Mendoza, A, Haagensen, EJ, Kokkalis, A, Roumelioti, F-M, Gagos, S, Tzetis, M, Canovas, B, Igea, A, Ahuja, AK, Zellweger, R, Havaki, S, Kanavakis, E, Kletsas, D, Roninson, IB, Garbis, SD, Lopes, M, Nebreda, A, Thanos, D, Blow, JJ, Townsend, P, Sørensen, CS, Bartek, J & Gorgoulis, VG 2016, 'Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing', Nature Cell Biology, vol. 18, no. 7, pp. 777-89. https://doi.org/10.1038/ncb3378

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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.",

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AU - Galanos, Panagiotis

AU - Vougas, Konstantinos

AU - Walter, David

AU - Polyzos, Alexander

AU - Maya-Mendoza, Apolinar

AU - Haagensen, Emma J

AU - Kokkalis, Antonis

AU - Roumelioti, Fani-Marlen

AU - Gagos, Sarantis

AU - Tzetis, Maria

AU - Canovas, Begoña

AU - Igea, Ana

AU - Ahuja, Akshay K

AU - Zellweger, Ralph

AU - Havaki, Sofia

AU - Kanavakis, Emanuel

AU - Kletsas, Dimitris

AU - Roninson, Igor B

AU - Garbis, Spiros D

AU - Lopes, Massimo

AU - Nebreda, Angel

AU - Thanos, Dimitris

AU - Blow, J Julian

AU - Townsend, Paul

AU - Sørensen, Claus Storgaard

AU - Bartek, Jiri

AU - Gorgoulis, Vassilis G

PY - 2016/6/28

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N2 - 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.

AB - 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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DO - 10.1038/ncb3378

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SN - 1465-7392

VL - 18

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EP - 789

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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