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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In CIP1-overexpressing TP53-null cultured cancer cells, a transient senescent state was entered but quickly escaped with enhanced cancer stem cell properties and an aggressive phenotype.
“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]
The Results section (page unavailable) reports that p21/CIP1-induced cells in a p53-null model initially became senescent, then a subpopulation escaped and showed greater invasiveness and anchorage-independent growth. It links altered gene expression to cancer “stemness,” but does not establish that the escaped cells had enhanced cancer stem cell properties. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAlthough the senescence cell-cycle arrest is generally irreversible, cell-cycle re-entry can occur under certain circumstances, particularly in tumor cells.
“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
Because p21 overexpression caused downregulation of RAD51, DSBs were processed by error-prone pathways including RAD52-dependent break-induced replication and single-strand annealing, and possibly nonhomologous end-joining.
“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]
These observations indicate a pro-oncogenic role of p21, at least in p53-negative cancer.
“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]
Replication-fork progression was asymmetric and slow, and DSBs accumulated in a manner that depended on CDT1 and CDC6 overexpression.
“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]
p21-overexpressing cells acquired the capacity to rereplicate.
“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]
Dependency on PCNA was confirmed using a p21 mutant with a disrupted PIP box, which did not cause CDT1 and CDC6 upregulation.
“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]
Unexpected colocalization of p21 and ki67 was observed in approximately 5% to 7% of cells within p53-deficient tumors.
“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]
Although the cell cycle arrest in cellular senescence is believed to be irreversible, senescent cells can under certain circumstances re-enter the cell cycle, such as in tumor cells, or be reprogrammed into induced pluripotent stem cells.
“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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Cites
1 retracted
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus
González, S., Klatt, P., Delgado, S., Conde, E., López‐Ríos, F., Sánchez‐Céspedes, M., Méndez, J., Antequera, F., & Serrano, M. (2006) · Nature · doi:10.1038/nature04585 · Cited by 186 · see citing works
RetractedThe Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
p21 in cancer: Intricate networks and multiple activities
Abbas, T., & Dutta, A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2657 · Cited by 2,712 · see citing works
Massive genomic rearrangement acquired in a single catastrophic event during cancer development
Stephens, P. J., Greenman, C. D., Fu, B., Yang, F., Bignell, G. R., Mudie, L. J., Pleasance, E. D., Lau, K. W., Beare, D., Stebbings, L. A., et al. (2011) · Cell · doi:10.1016/j.cell.2010.11.055 · Cited by 2,414 · see citing works
Genomic instability — an evolving hallmark of cancer
Negrini, S., Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2858 · Cited by 2,397 · see citing works
Self-citationThe causes and consequences of genetic heterogeneity in cancer evolution
Burrell, R. A., McGranahan, N., Bartek, J., & Swanton, C. (2013) · Nature · doi:10.1038/nature12625 · Cited by 2,262 · see citing works
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986 · see citing works
Self-citationAn Oncogene-Induced DNA Damage Model for Cancer Development
Halazonetis, T. D., Gorgoulis, V. G., & Bartek, J. (2008) · Science · doi:10.1126/science.1140735 · Cited by 1,851 · see citing works
Self-citationBreakDancer: an algorithm for high-resolution mapping of genomic structural variation
Chen, K., Wallis, J. W., McLellan, M. D., Larson, D. E., Kalicki, J. M., Pohl, C. S., McGrath, S. D., Wendl, M. C., Zhang, Q., Locke, D. P., et al. (2009) · Nature Methods · doi:10.1038/nmeth.1363 · Cited by 1,463 · see citing works
Reversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457 · see citing works
Ackerman, L. V., & Rosaí, J. (1974) · Medical Entomology and Zoology · Cited by 1,042 · see citing works
Rivlin, N., Brosh, R., Oren, M., & Rotter, V. (2011) · Genes & Cancer · doi:10.1177/1947601911408889 · Cited by 1,033 · see citing works
Using the Student's t-test with extremely small sample sizes
de Winter, J. C. F. (2013) · University of Massachusetts Amherst · doi:10.7275/e4r6-dj05 · Cited by 992 · see citing works
A faster circular binary segmentation algorithm for the analysis of array CGH data
Venkatraman, E. S., & Olshen, A. B. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btl646 · Cited by 963 · see citing works
Pines, J., & Hunter, T. R. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.115.1.1 · Cited by 867 · see citing works
Agarwal, M. L., Agarwal, A., Taylor, W. R., & Stark, G. R. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.18.8493 · Cited by 858 · see citing works
Nucleotide deficiency promotes genomic instability in early stages of cancer development
Bester, A. C., Roniger, M., Oren, Y. S., Im, M. M., Sarni, D., Chaoat, M., Bensimon, A., Zamir, G., Shewach, D. S., & Kerem, B. (2011) · Cell · doi:10.1016/j.cell.2011.03.044 · Cited by 858 · see citing works
Hastings, P. J., Ira, G., & Lupski, J. R. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000327 · Cited by 818 · see citing works
Niculescu, A. B., Chen, X., Smeets, M. F. M. A., Hengst, L., Prives, C. L., & Reed, S. I. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.1.629 · Cited by 725 · see citing works
Regulation of NF-κB by Cyclin-Dependent Kinases Associated with the p300 Coactivator
Perkins, N. D., Felzien, L. K., Betts, J. C., Leung, K., Beach, D., & Nabel, G. J. (1997) · Science · doi:10.1126/science.275.5299.523 · Cited by 722 · see citing works
Preventing re-replication of chromosomal DNA
Blow, J. J., & Dutta, A. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1663 · Cited by 664 · see citing works
Self-citationRad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells
Zellweger, R., Dalcher, D., Mutreja, K., Berti, M., Schmid, J. A., Herrador, R., Vindigni, A., & Lopes, M. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201406099 · Cited by 660 · see citing works
Self-citationHallmarks of senescence in carcinogenesis and cancer therapy
Shay, J. W., & Roninson, I. B. (2004) · Oncogene · doi:10.1038/sj.onc.1207518 · Cited by 502 · see citing works
Self-citationReplication fork reversal in eukaryotes: from dead end to dynamic response
Neelsen, K. J., & Lopes, M. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3935 · Cited by 494 · see citing works
Self-citationCooks, T., Pateras, I. S., Tarcic, O., Solomon, H., Schetter, A. J., Wilder, S., Lozano, G., Pikarsky, E., Forshew, T., Rozenfeld, N., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.03.022 · Cited by 471 · see citing works
Self-citationRoninson, I. B. (2002) · Cancer Letters · doi:10.1016/s0304-3835(01)00847-3 · Cited by 443 · see citing works
Self-citationNuclear Dynamics of PCNA in DNA Replication and Repair
Essers, J., Theil, A. F., Baldeyron, C., van Cappellen, W. A., Houtsmuller, A. B., Kanaar, R., & Vermeulen, W. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9350-9359.2005 · Cited by 442 · see citing works
Identification of Early Replicating Fragile Sites that Contribute to Genome Instability
Barlow, J. H., Faryabi, R. B., Callén, E., Wong, N., Malhowski, A. J., Chen, H. T., Gutierrez-Cruz, G., Sun, H., McKinnon, P. J., Wright, G. W., et al. (2013) · Cell · doi:10.1016/j.cell.2013.01.006 · Cited by 433 · see citing works
ATR phosphorylates SMARCAL1 to prevent replication fork collapsePreprint
Couch, F. B., Bansbach, C. E., Driscoll, R., Luzwick, J. W., Glick, G. G., Betous, R., Carroll, C. M., Jung, S. Y., Qin, J., Cimprich, K. A., et al. (2013) · Genes & Development · doi:10.1101/gad.214080.113 · Cited by 409 · see citing works
A p53-Dependent Checkpoint Pathway Prevents Rereplication
Vaziri, C., Saxena, S., Jeon, Y., Lee, C., Murata, K., Machida, Y., Wagle, N., Hwang, D. S., & Dutta, A. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00099-6 · Cited by 393 · see citing works
Two E3 ubiquitin ligases, SCF‐Skp2 and DDB1‐Cul4, target human Cdt1 for proteolysis
Nishitani, H., Sugimoto, N., Roukos, V., Nakanishi, Y., Saijo, M., Obuse, C., Tsurimoto, T., Nakayama, K., Nakayama, K., Fujita, M., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601002 · Cited by 392 · see citing works
Hanada, K., Budzowska, M., Davies, S. L., van Drunen, E., Onizawa, H., Beverloo, H. B., Maas, A., Essers, J., Hickson, I. D., & Kanaar, R. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1313 · Cited by 392 · see citing works
Georgakopoulou, E., Tsimaratou, K., Evangelou, K., Fernandez, M.-P., Zoumpourlis, V, Trougakos, I., Kletsas, D., Bartek, J., Serrano, M., & Gorgoulis, V. (2012) · Aging · doi:10.18632/aging.100527 · Cited by 390 · see citing works
Self-citationChang, B.-D., Xuan, Y., Broude, E. V., Zhu, H., Schott, B., Fang, J., & Roninson, I. B. (1999) · Oncogene · doi:10.1038/sj.onc.1203078 · Cited by 382 · see citing works
Self-citationMailand, N., & Diffley, J. (2005) · Cell · doi:10.1016/j.cell.2005.08.013 · Cited by 373 · see citing works
Abbas, T., Sivaprasad, U., Terai, K., Amador, V., Pagano, M., & Dutta, A. (2008) · Genes & Development · doi:10.1101/gad.1676108 · Cited by 367 · see citing works
Pathways of mammalian replication fork restart
Petermann, E., & Helleday, T. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2974 · Cited by 340 · see citing works
Marti, A., Wirbelauer, C., Scheffner, M., & Krek, W. (1999) · Nature Cell Biology · doi:10.1038/8984 · Cited by 318 · see citing works
Id proteins in cell growth and tumorigenesis
Sikder, H. A., Devlin, M. K., Dunlap, S., Ryu, B., & Alani, R. M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00141-7 · Cited by 309 · see citing works
Holland, A. J., & Cleveland, D. W. (2012) · Nature Medicine · doi:10.1038/nm.2988 · Cited by 304 · see citing works
Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells
Viale, A., Franco, F., Orleth, A., Cambiaghi, V., Giuliani, V., Bossi, D., Ronchini, C., Ronzoni, S., Muradore, I., Monestiroli, S., et al. (2008) · Nature · doi:10.1038/nature07618 · Cited by 303 · see citing works
Warfel, N. A., & El‐Deiry, W. S. (2012) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32835b639e · Cited by 287 · see citing works
Bischoff, F. Z., Yim, S. O., Pathak, S., Grant, G., Siciliano, M. J., Giovanella, B. C., Strong, L. C., & Tainsky, M. A. (1990) · PubMed · Cited by 252 · see citing works
Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangementsPreprint
Zhang, C.-Z., Leibowitz, M. L., & Pellman, D. (2013) · Genes & Development · doi:10.1101/gad.229559.113 · Cited by 241 · see citing works
Kim, Y., Starostina, N. G., & Kipreos, E. T. (2008) · Genes & Development · doi:10.1101/gad.1703708 · Cited by 240 · see citing works
Cyclin-Dependent Kinases and S Phase Control in Mammalian Cells
Woo, R. A., & Poon, R. Y. C. (2003) · Cell Cycle · doi:10.4161/cc.2.4.468 · Cited by 234 · see citing works
Replication licensing and cancer — a fatal entanglement?
Blow, J. J., & Gillespie, P. J. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2500 · Cited by 229 · see citing works
Self-citationMechanism of CRL4Cdt2, a PCNA-dependent E3 ubiquitin ligasePreprint
Havens, C. G., & Walter, J. C. (2011) · Genes & Development · doi:10.1101/gad.2068611 · Cited by 223 · see citing works
Deregulated Overexpression of hCdt1 and hCdc6 Promotes Malignant Behavior
Liontos, M., Koutsami, M., Sideridou, M., Evangelou, K., Kletsas, D., Levy, B., Kotsinas, A., Nahum, O., Zoumpourlis, V. C., Kouloukoussa, M., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2837 · Cited by 217 · see citing works
Self-citationGenomic Instability in CancerPreprint
Abbas, T., Keaton, M., & Dutta, A. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012914 · Cited by 200 · see citing works
Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function
Schlisio, S., Halperin, T., Vidal, M., & Nevins, J. R. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf577 · Cited by 197 · see citing works
DNA replication and progression through S phase
Takeda, D. Y., & Dutta, A. (2005) · Oncogene · doi:10.1038/sj.onc.1208616 · Cited by 193 · see citing works
The role of microhomology in genomic structural variation
Ottaviani, D., LeCain, M., & Sheer, D. (2014) · Trends in Genetics · doi:10.1016/j.tig.2014.01.001 · Cited by 188 · see citing works
Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates
Neelsen, K. J., Zanini, I. M. Y., Herrador, R., & Lopes, M. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201212058 · Cited by 188 · see citing works
Self-citationKarakaidos, P., Taraviras, S. L., Vassiliou, L. V., Zacharatos, P., Kastrinakis, N. G., Kougiou, D., Kouloukoussa, M., Nishitani, H., Papavassiliou, A. G., Lygerou, Z., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63393-7 · Cited by 180 · see citing works
Self-citationChan, J. K. C. (1990) · Histopathology · doi:10.1111/j.1365-2559.1990.tb01104.x · Cited by 180 · see citing works
Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression
Bates, S., Ryan, K. M., Phillips, A. C., & Vousden, K. H. (1998) · Oncogene · doi:10.1038/sj.onc.1202104 · Cited by 176 · see citing works
Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase
Beck, H., Nähse, V., Larsen, M. S. Y., Groth, P., Clancy, T., Lees, M. J., Jørgensen, M., Helleday, T., Syljuåsen, R. G., & Sørensen, C. S. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200905059 · Cited by 169 · see citing works
Self-citationp57KIP2: “Kip”ing the Cell under Control
Pateras, I. S., Apostolopoulou, K., Niforou, K., Kotsinas, A., & Gorgoulis, V. G. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0317 · Cited by 150 · see citing works
Self-citationWang, Y., Blandino, G., & Givol, D. (1999) · Oncogene · doi:10.1038/sj.onc.1202632 · Cited by 142 · see citing works
Velimezi, G., Liontos, M., Vougas, K., Roumeliotis, T., Bartkova, J., Sideridou, M., Dereli-Oz, A., Kocylowski, M., Pateras, I. S., Evangelou, K., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2795 · Cited by 131 · see citing works
Self-citationSET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation
Jørgensen, S., Eskildsen, M., Fugger, K., Hansen, L., Larsen, M. S. Y., Kousholt, A. N., Syljuåsen, R. G., Trelle, M. B., Jensen, O. N., Helin, K., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201009076 · Cited by 128 · see citing works
Self-citationCha, H. H., Cram, E. J., Wang, E. C., Huang, A. J., Kasler, H. G., & Firestone, G. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.4.1998 · Cited by 125 · see citing works
Cytotoxicity and estrogenicity of Invisalign appliances
Eliades, T., Pratsinis, H., Athanasiou, A. E., Eliades, G., & Kletsas, D. (2009) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/j.ajodo.2009.03.006 · Cited by 117 · see citing works
Self-citationDNA lesions sequestered in micronuclei induce a local defective-damage response
Terradas, M., Martı́n, M., Tusell, L., & Genescà, A. (2009) · DNA repair · doi:10.1016/j.dnarep.2009.07.004 · Cited by 109 · see citing works
A network of p73, p53 and Egr1 is required for efficient apoptosis in tumor cells
Yu, J., Baron, V. T., Mercola, D., Mustelin, T., & Adamson, E. D. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402029 · Cited by 101 · see citing works
p53 activates ICAM‐1 (CD54) expression in an NF‐κB‐independent manner
Gorgoulis, V. G., Zacharatos, P., Kotsinas, A., Kletsas, D., Mariatos, G., Zoumpourlis, V., Ryan, K. M., Kittas, C. N., & Papavassiliou, A. G. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg157 · Cited by 100 · see citing works
Self-citationCdc6 expression represses E-cadherin transcription and activates adjacent replication origins
Sideridou, M., Zakopoulou, R., Evangelou, K., Liontos, M., Kotsinas, A., Rampakakis, E., Gagos, S., Kahata, K., Grabušić, K., Gkouskou, K. K., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201108121 · Cited by 98 · see citing works
Self-citationp53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes
Benson, E. K., Mungamuri, S. K., Attie, O., Kracikova, M., Sachidanandam, R., Manfredi, J. J., & Aaronson, S. A. (2013) · Oncogene · doi:10.1038/onc.2013.378 · Cited by 95 · see citing works
Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA templatePreprint
Neelsen, K. J., Zanini, I. M. Y., Mijic, S., Herrador, R., Zellweger, R., Chaudhuri, A. R., Creavin, K., Blow, J. J., & Lopes, M. (2013) · Genes & Development · doi:10.1101/gad.226373.113 · Cited by 95 · see citing works
Self-citationRad51 Protein Controls Rad52-mediated DNA Annealing
Wu, Y., Kantake, N., Sugiyama, T., & Kowalczykowski, S. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801097200 · Cited by 90 · see citing works
Recovery of Arrested Replication Forks by Homologous Recombination Is Error-Prone
Iraqui, I., Chekkal, Y., Jmari, N., Pietrobon, V., Fréon, K., Costes, A., & Lambert, S. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002976 · Cited by 89 · see citing works
p53-Dependent Regulation of Cdc6 Protein Stability Controls Cellular Proliferation
Duursma, A. M., & Agami, R. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.6937-6947.2005 · Cited by 77 · see citing works
Neelsen, K. J., Chaudhuri, A. R., Follonier, C., Herrador, R., & Lopes, M. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-706-8_15 · Cited by 69 · see citing works
Self-citationCDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells
Delehouzé, C., Godl, K., Loaëc, N., Bruyère, C., Desban, N., Oumata, N., Galons, H., Roumeliotis, T. I., Γιαννοπούλου, Ε., Grenet, J. A., et al. (2013) · Oncogene · doi:10.1038/onc.2013.513 · Cited by 69 · see citing works
Self-citationEvangelou, K., Bartkova, J., Kotsinas, A., Pateras, I. S., Liontos, M., Velimezi, G., Kosar, M., Liloglou, T., Trougakos, I. P., Dyrskjot, L., et al. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.76 · Cited by 59 · see citing works
Self-citationGibbs, E., Kelman, Z., Gulbis, J. M., O’Donnell, M. E., Kuriyan, J., Burgers, P., & Hurwitz, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.4.2373 · Cited by 58 · see citing works
Garbis, S. D., Roumeliotis, T. I., Tyritzis, S. Ι., Zorpas, K. M., Pavlakis, K., & Constantinides, C. A. (2010) · Analytical Chemistry · doi:10.1021/ac102075d · Cited by 55 · see citing works
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Peart, M. J., Poyurovsky, M. V., Kass, E. M., Urist, M. J., Verschuren, E. W., Summers, M. K., Jackson, P. K., & Prives, C. L. (2010) · Cell Cycle · doi:10.4161/cc.9.19.13162 · Cited by 52 · see citing works
Liontos, M., Niforou, K., Velimezi, G., Vougas, K. N., Evangelou, K., Apostolopoulou, K., Vrtěl, R., Damalas, A. F., Kontovazenitis, P., Kotsinas, A., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.081160 · Cited by 48 · see citing works
Self-citationThe WRN and MUS81 proteins limit cell death and genome instability following oncogene activation
Murfuni, I., Nicolai, S., Baldari, S., Crescenzi, M., Bignami, M., Franchitto, A., & Pichierri, P. (2012) · Oncogene · doi:10.1038/onc.2012.80 · Cited by 45 · see citing works
Exploring and exploiting the systemic effects of deregulated replication licensing
Petrakis, T. G., Komseli, E.-S., Papaioannou, M. D., Vougas, K., Polyzos, A., Myrianthopoulos, V., Mikros, E., Trougakos, I. P., Thanos, D., Branzei, D., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.12.002 · Cited by 44 · see citing works
Self-citationRegulation of E2F1 by APC/CCdh1via K11 linkage-specific ubiquitin chain formation
Budhavarapu, V. N., White, E., Mahanic, C. S., Chen, L., Lin, F., & Lin, W.-C. (2012) · Cell Cycle · doi:10.4161/cc.20643 · Cited by 41 · see citing works
Gorgoulis, V. G., Zacharatos, P., Kotsinas, A., Mariatos, G., Liloglou, T., Vogiatzi, T., Foukas, P., Rassidakis, G. Z., Garinis, G. A., Ioannides, T., et al. (2000) · Molecular Medicine · doi:10.1007/bf03402115 · Cited by 38 · see citing works
Self-citationPreventing DNA over-replication: a Cdk perspective
Porter, A. C. G. (2008) · Cell Division · doi:10.1186/1747-1028-3-3 · Cited by 37 · see citing works
Papachristou, E. K., Roumeliotis, T. I., Chrysagi, A., Trigoni, C., Charvalos, E., Townsend, P. A., Pavlakis, K., & Garbis, S. D. (2013) · Journal of Proteome Research · doi:10.1021/pr301067r · Cited by 35 · see citing works
Self-citationSakellariou, D., Chiourea, M., Raftopoulou, C., & Gagos, S. (2013) · Neoplasia · doi:10.1593/neo.131574 · Cited by 27 · see citing works
Self-citationStatsDB: platform-agnostic storage and understanding of next generation sequencing run metrics
Ramirez-Gonzalez, R. H., Leggett, R. M., Waite, D., Thanki, A. S., Drou, N., Cáccamo, M., & Davey, R. (2013) · F1000Research · doi:10.12688/f1000research.2-248.v1 · Cited by 18 · see citing works
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Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · see citing works
Self-citationMechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Cell cycle regulation: p53-p21-RB signaling
Engeland, K. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00988-z · Cited by 1,308 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
p21: a two-faced genome guardian.
Georgakilas, A. G., Martin, O. A., & Bonner, W. M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.02.001 · Cited by 489 · see citing works
GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability
Hu, W. L., Jin, L., Xu, A., Wang, Y. F., Thorne, R. F., Zhang, X. D., & Wu, M. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0066-7 · Cited by 348 · see citing works
Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency
Cong, K., Peng, M., Kousholt, A. N., Lee, W. T. C., Lee, S., Nayak, S. U., Krais, J. J., VanderVere-Carozza, P. S., Pawelczak, K. S., Calvo, J. A., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.06.011 · Cited by 348 · see citing works
Shamloo, B., & Usluer, S. (2019) · Cancers · doi:10.3390/cancers11081178 · Cited by 336 · see citing works
Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments
Yip, H. Y. K., & Papa, A. (2021) · Cells · doi:10.3390/cells10030659 · Cited by 332 · see citing works
The Multifaceted p21 (Cip1/Waf1/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy
Kreis, N., Louwen, F., & Yuan, J. (2019) · Cancers · doi:10.3390/cancers11091220 · Cited by 309 · see citing works
Simpson, S., Dunning, M., de Brot, S., Grau‐Roma, L., Mongan, N. P., & Rutland, C. S. (2017) · Acta veterinaria Scandinavica · doi:10.1186/s13028-017-0341-9 · Cited by 294 · see citing works
Cellular senescence and SASP in tumor progression and therapeutic opportunities
Dong, Z., Luo, Y., Yuan, Z., Tian, Y., Jin, T., & Feng, X. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02096-7 · Cited by 292 · see citing works
Robust, universal biomarker assay to detect senescent cells in biological specimens
Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., Kastrinakis, N. G., Pouli, N., Marakos, P., Townsend, P., et al. (2017) · Aging Cell · doi:10.1111/acel.12545 · Cited by 259 · see citing works
Self-citationMammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks
Sotiriou, S. K., Kamileri, I., Lugli, N., Evangelou, K., Da‐Ré, C., Huber, F., Padayachy, L., Tardy, S., Nicati, N. L., Barriot, S., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.038 · Cited by 248 · see citing works
Self-citationMitochondrial Homeostasis and Cellular Senescence
Vasileiou, P. V. S., Evangelou, K., Vlasis, K. G., Fildisis, G., Panayiotidis, M. I., Chronopoulos, E., Passias, P.-G., Kouloukoussa, M., Gorgoulis, V. G., & Havaki, S. (2019) · Cells · doi:10.3390/cells8070686 · Cited by 246 · see citing works
Self-citationBreak-Induced Replication: The Where, The Why, and The How
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Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions
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Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
Kudlová, N., Sanctis, J. B. D., & Hajdúch, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084168 · Cited by 176 · see citing works
Endogenous Replication Stress in Mother Cells Leads to Quiescence of Daughter Cells
Arora, M., Moser, J. C., Phadke, H., Basha, A. A., & Spencer, S. L. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.055 · Cited by 165 · see citing works
DNA Damage Response and Autophagy: A Meaningful Partnership
Eliopoulos, A. G., Havaki, S., & Gorgoulis, V. G. (2016) · Frontiers in Genetics · doi:10.3389/fgene.2016.00204 · Cited by 169 · see citing works
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p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways
Lindström, M. S., Bártek, J., & Maya‐Mendoza, A. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00999-w · Cited by 161 · see citing works
Self-citationSenescence and senotherapeutics: a new field in cancer therapy
Myrianthopoulos, V., Evangelou, K., Vasileiou, P. V. S., Cooks, T., Vassilakopoulos, T. P., Pangalis, G. A., Kouloukoussa, M., Kittas, C., Georgakilas, A. G., & Gorgoulis, V. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.006 · Cited by 160 · see citing works
Self-citationExtracellular matrix alterations in senescent cells and their significance in tissue homeostasis
Mavrogonatou, E., Pratsinis, H., Papadopoulou, A., Karamanos, N. K., & Kletsas, D. (2019) · Matrix Biology · doi:10.1016/j.matbio.2017.10.004 · Cited by 153 · see citing works
Self-citationSu, W., Feng, S., Chen, X., Yang, X., Mao, R., Guo, C., Wang, Z., Thomas, D. G., Lin, J., Reddy, R. M., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0222 · Cited by 147 · see citing works
SIRF: Quantitative in situ analysis of protein interactions at DNA replication forks
Roy, S., Luzwick, J. W., & Schlacher, K. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201709121 · Cited by 138 · see citing works
Break induced replication in eukaryotes: mechanisms, functions, and consequences
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The Fountain of Youth by Targeting Senescent Cells?
de Keizer, P. L. J. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.11.006 · Cited by 127 · see citing works
Flavonoids—Natural Gifts to Promote Health and Longevity
Fan, X., Fan, Z., Yang, Z., Huang, T., Tong, Y., Yang, D., Mao, X., & Yang, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042176 · Cited by 127 · see citing works
Evangelou, K., & Gorgoulis, V. G. (2017) · Methods in Molecular Biology · doi:10.1007/978-1-4939-6670-7_10 · Cited by 124 · see citing works
Self-citationVougas, K. N., Sakellaropoulos, T., Kotsinas, A., Foukas, G.-R. P., Ntargaras, A., Koinis, F., Polyzos, A., Myrianthopoulos, V., Zhou, H., Narang, S., et al. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107395 · Cited by 124 · see citing works
Self-citationRegulation and Function of Cdt1; A Key Factor in Cell Proliferation and Genome Stability
Pozo, P. N., & Cook, J. G. (2016) · Genes · doi:10.3390/genes8010002 · Cited by 123 · see citing works
Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem
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Self-citationReplication Licensing Aberrations, Replication Stress, and Genomic Instability
Petropoulos, M., Tsaniras, S. C., Taraviras, S. L., & Lygerou, Z. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.03.011 · Cited by 121 · see citing works
CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
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Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents
Bojko, A., Czarnecka‐Herok, J., Charzyńska, A., Dąbrowski, M., & Sikora, E. (2019) · Cells · doi:10.3390/cells8121501 · Cited by 109 · see citing works
Integrating the DNA damage and protein stress responses during cancer development and treatment
Gorgoulis, V. G., Pefani, D., Pateras, I. S., & Trougakos, I. P. (2018) · The Journal of Pathology · doi:10.1002/path.5097 · Cited by 108 · see citing works
Self-citationLife or Death after a Break: What Determines the Choice?
Krenning, L., van den Berg, J., & Medema, R. H. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.08.023 · Cited by 108 · see citing works
Biological functions of therapy-induced senescence in cancer
Fitsiou, E., Soto-Gamez, A., & Demaria, M. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.021 · Cited by 101 · see citing works
Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity
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Cellular senescence in cancer: clinical detection and prognostic implications
Domen, A., Deben, C., Verswyvel, J., Flieswasser, T., Prenen, H., Peeters, M., Lardon, F., & Wouters, A. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02555-3 · Cited by 94 · see citing works
Sheikh, B. Y., Sarker, M. M. R., Kamarudin, M. N. A., & Mohan, G. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.10.038 · Cited by 91 · see citing works
Zampetidis, C., Galanos, P., Angelopoulou, A., Zhu, Y., Polyzou, A., Karamitros, T., Kotsinas, A., Lаgopati, N., Mourkioti, I., Mirzazadeh, R., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.10.017 · Cited by 90 · see citing works
Self-citationManousopoulou, A., Gatherer, M., Smith, C., Nicoll, J. A. R., Woelk, C. H., Johnson, M., Kalaria, R. N., Attems, J., Garbis, S. D., & Carare, R. O. (2016) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12342 · Cited by 87 · see citing works
Self-citationATF3 drives senescence by reconstructing accessible chromatin profiles
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p53 Activity Results in DNA Replication Fork Processivity
Klusmann, I., Rodewald, S., Müller, L., Friedrich, M., Wienken, M., Li, Y., Schulz‐Heddergott, R., & Dobbelstein, M. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.036 · Cited by 82 · see citing works
Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis
Chin, C., Ravichandran, R., Sanborn, K., Fleming, T. P., Wheatcroft, S. B., Kearney, M. T., Tokman, S., Walia, R., Smith, M. A., Flint, D. J., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.100945 · Cited by 80 · see citing works
Ding, F., Lu, L., Wu, C., Pan, X., Liu, B., Zhang, Y., Wang, Y., Wu, W., Yan, B., Zhang, Y., et al. (2022) · Theranostics · doi:10.7150/thno.77630 · Cited by 81 · see citing works
Liu, B., Peng, Z., Zhang, H., Zhang, N., Liu, Z., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02284-z · Cited by 82 · see citing works
RB, p130 and p107 differentially repress G1/S and G2/M genes after p53 activation
Schade, A. E., Fischer, M., & DeCaprio, J. A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz961 · Cited by 74 · see citing works
Peng, Z., Chen, L., Nussler, A. K., Liu, L., & Yang, W. Q. (2016) · Journal of Applied Toxicology · doi:10.1002/jat.3428 · Cited by 74 · see citing works
Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis
Blander, H. D., Morel, A., Senaratne, A. P., Ouzounova, M., & Puisieux, A. (2021) · Cancers · doi:10.3390/cancers13184561 · Cited by 74 · see citing works
CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?
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Cooperative p16 and p21 action protects female astrocytes from transformation
Kfoury, N., Sun, T., Yu, K., Rockwell, N., Tinkum, K. L., Qi, Z., Warrington, N. M., McDonald, P. R., Roy, A., Weir, S. J., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0513-5 · Cited by 70 · see citing works
Ticli, G., Cazzalini, O., Stivala, L. A., & Prosperi, E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137058 · Cited by 69 · see citing works
Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability
Galanos, P., Pappas, G., Polyzos, A., Kotsinas, A., Svolaki, I., Giakoumakis, N. N., Glytsou, C., Pateras, I. S., Swain, U., Souliotis, V. L., et al. (2018) · Genome Biology · doi:10.1186/s13059-018-1401-9 · Cited by 67 · see citing works
Self-citationSenescence in chronic wounds and potential targeted therapies
Wei, X., Li, M., Zheng, Z., Ma, J., Gao, Y., Chen, L., Peng, Y., Yu, S., & Yang, L. (2021) · Burns & Trauma · doi:10.1093/burnst/tkab045 · Cited by 64 · see citing works
The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy
Cao, L., Li, K., Li, Q., Tong, Q., Wang, Y., & Huang, L. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02475-8 · Cited by 70 · see citing works
Černá, K. A., Oppelt, J., Chochola, V., Musilová, K., Šeda, V., Pavlasová, G. M., Radová, L., Arigoni, M., Calogero, R., Beneš, V., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0230-x · Cited by 64 · see citing works
Magkouta, S., Veroutis, D., Pousias, A., Papaspyropoulos, A., Pippa, N., Lougiakis, N., Kambas, K., Lagopati, N., Polyzou, A., Georgiou, M., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.09.006 · Cited by 59 · see citing works
Self-citationHMGB1 modulates the balance between senescence and apoptosis in response to genotoxic stress
Lee, J., Park, I. H., Rhee, W. J., Kim, H. S., & Shin, J. (2019) · The FASEB Journal · doi:10.1096/fj.201900288r · Cited by 57 · see citing works
RAD52: Paradigm of Synthetic Lethality and New Developments
Rossi, M. J., DiDomenico, S. F., Patel, M., & Mazin, A. V. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.780293 · Cited by 55 · see citing works
Magkouta, S., Veroutis, D., Papaspyropoulos, A., Georgiou, M., Lougiakis, N., Pippa, Ν., Havaki, S., Palaiologou, A., Thanos, D.-F., Kambas, K., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00747-4 · Cited by 62 · see citing works
Self-citationLiu, P., Wang, L., & Yu, H. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1410637 · Cited by 56 · see citing works
Escape from senescence: molecular basis and therapeutic ramifications
Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023) · The Journal of Pathology · doi:10.1002/path.6164 · Cited by 55 · see citing works
Self-citationIFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma
Homann, L., Rentschler, M., Brenner, E., Böhm, K., Röcken, M., & Wieder, T. (2022) · Cells · doi:10.3390/cells11091514 · Cited by 52 · see citing works
Wang, J., Wang, Y., Mei, H., Yin, Z., Geng, Y., Zhang, T., Wu, G., & Lin, Z. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.01.031 · Cited by 52 · see citing works
Komseli, E.-S., Pateras, I. S., Krejsgaard, T., Stawiski, K., Rizou, S. V., Polyzos, A., Roumelioti, F., Chiourea, M., Mourkioti, I., Paparouna, E., et al. (2018) · BMC Genomics · doi:10.1186/s12864-017-4375-1 · Cited by 49 · see citing works
Self-citationHjorth-Jensen, K., Maya‐Mendoza, A., Dalgaard, N., Sigurðsson, J. O., Bártek, J., Iglesias‐Gato, D., Olsen, J. V., & Flores‐Morales, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky719 · Cited by 51 · see citing works
Self-citationGhorai, A., Mahaddalkar, T., Thorat, R. A., & Dutt, S. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.06.023 · Cited by 48 · see citing works
The paradox of senescent-marker positive cancer cells: challenges and opportunities
O’Sullivan, E. A., Wallis, R., Mossa, F., & Bishop, C. L. (2024) · npj Aging · doi:10.1038/s41514-024-00168-y · Cited by 49 · see citing works
Role of genomic instability in human carcinogenesis
Moon, J. J., Lu, A., & Moon, C. (2019) · Experimental Biology and Medicine · doi:10.1177/1535370219826031 · Cited by 46 · see citing works
Sheng, C., Mendler, I.-H., Rieke, S., Snyder, P., Jentsch, M., Friedrich, D., Drossel, B., & Loewer, A. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.031 · Cited by 45 · see citing works
Mourikis, T. P., Benedetti, L. G., Foxall, E., Temelkovski, D., Nulsen, J., Perner, J., Cereda, M., Lagergren, J., Howell, M. T., Yau, C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10898-3 · Cited by 42 · see citing works
Hidalgo, K. J. R., Carmello, J. C., Jordão, C. C., Barbugli, P. A., Costa, C. A. D. S., Mima, E. G. D. O., & Pavarina, A. C. (2019) · Pharmaceuticals · doi:10.3390/ph12030140 · Cited by 44 · see citing works
CRL4Cdt2: Coupling Genome Stability to Ubiquitination
Παναγόπουλος, Α., Taraviras, S. L., Nishitani, H., & Lygerou, Z. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.01.005 · Cited by 44 · see citing works
Wang, J., Shao, F., Yu, Q., Ye, L., Wusiman, D., Wu, R., Tuo, Z., Wang, Z., Li, D., Cho, W. C. S., et al. (2025) · Research · doi:10.34133/research.0612 · Cited by 42 · see citing works
Proteome Stability as a Key Factor of Genome Integrity
Gumeni, S., Evangelakou, Z., Gorgoulis, V. G., & Trougakos, I. P. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102036 · Cited by 41 · see citing works
Self-citationNFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation
Nicolae, C. M., O’Connor, M. J., Constantin, D., & Moldovan, G. (2018) · Oncogene · doi:10.1038/s41388-018-0219-y · Cited by 42 · see citing works
Single-Strand Annealing in Cancer
Błasiak, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042167 · Cited by 42 · see citing works
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Curti, L., & Campaner, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126168 · Cited by 42 · see citing works
Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells
Morsli, S., Doherty, G. J., & Muñoz‐Espín, D. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111618 · Cited by 41 · see citing works
Senescent cells at the crossroads of aging, disease, and tissue homeostasis
Kuehnemann, C., & Wiley, C. D. (2023) · Aging Cell · doi:10.1111/acel.13988 · Cited by 41 · see citing works
Nayak, D., Kumar, A., Chakraborty, S., Rasool, R. U., Amin, H., Katoch, A., Gopinath, V., Mahajan, V., Zilla, M. K., Rah, B., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.70 · Cited by 40 · see citing works
Galata, E., Georgakopoulou, E. A., Kassalia, M.-E., Papadopoulou-Fermeli, N., & Pavlatou, E. A. (2019) · Materials · doi:10.3390/ma12162589 · Cited by 40 · see citing works
Manousopoulou, A., Hayden, A. L., Mellone, M., Garay‐Baquero, D. J., White, C., Noble, F., López, M. E. P., Thomas, G. J., Underwood, T., & Garbis, S. D. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0042-9 · Cited by 39 · see citing works
Self-citationSenescence of Tumor Cells in Anticancer Therapy—Beneficial and Detrimental Effects
Piskorz, W. M., & Cechowska‐Pasko, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911082 · Cited by 39 · see citing works
In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias
Muñoz, S., Búa, S., Rodríguez‐Acebes, S., Megı́as, D., Ortega, S., Martino, A. D., & Méndez, J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.032 · Cited by 38 · see citing works
Beck, M., Schirmacher, P., & Singer, S. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.06.021 · Cited by 37 · see citing works
Yang, X., Liu, S., Xu, J., Cao, S.-G., Li, Y., & Zhou, Y. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.04.027 · Cited by 37 · see citing works
Airik, M., Phua, Y. L., Huynh, A. B., McCourt, B. T., Rush, B. M., Tan, R. J., Vockley, J. E., Murray, S. L., Dorman, A., Conlon, P. J., et al. (2022) · Kidney International · doi:10.1016/j.kint.2022.07.003 · Cited by 36 · see citing works
Romanov, V. S., & Rudolph, K. L. (2016) · Nature Cell Biology · doi:10.1038/ncb3382 · Cited by 36 · see citing works
Connecting cancer relapse with senescence
Pluquet, O., Abbadie, C., & Coqueret, O. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.08.004 · Cited by 37 · see citing works
Yu, Z., Sun, Y., She, X., Wang, Z., Chen, S., Deng, Z., Zhang, Y., Liu, Q., Liu, Q., Zhao, C., et al. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0483-2 · Cited by 36 · see citing works
Regulation of replication fork speed: Mechanisms and impact on genomic stability
Merchut‐Maya, J. M., Bártek, J., & Maya‐Mendoza, A. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.102654 · Cited by 34 · see citing works
Self-citationGonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma
Broestl, L., Warrington, N. M., Grandison, L., Abou-Antoun, T., Tung, O., Shenoy, S., Tallman, M. M., Rhee, G., Yang, W., Sponagel, J., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03743-9 · Cited by 35 · see citing works
Zhang, X., Feng, Y., Wang, X., Zhang, Y., Yuan, C., Zhang, S.-F., Shen, Y., Fu, Y., Zhou, C., Li, X. Y., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0137-x · Cited by 35 · see citing works
Oncogene-Induced Replication Stress Drives Genome Instability and Tumorigenesis
Sarni, D., & Kerem, B. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18071339 · Cited by 34 · see citing works
Boroujeni, S. M., Koontz, A., Tseropoulos, G., Kerosuo, L., Mehrotra, P., Bajpai, V. K., Selvam, S. R., Lei, P., Bronner-Fraser, M. E., & Andreadis, S. T. (2019) · Scientific Reports · doi:10.1038/s41598-019-46140-9 · Cited by 34 · see citing works
Function of p21 and its therapeutic effects in esophageal cancer (Review)
Wang, L., Han, H., Dong, L., Wang, Z., & Qin, Y. (2020) · Oncology Letters · doi:10.3892/ol.2020.12397 · Cited by 34 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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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