UV Irradiation Triggers Ubiquitin-Dependent Degradation of p21WAF1 to Promote DNA Repair
Open accessAbstract
p53-mediated increase in cyclin-dependent kinase inhibitor p21(WAF1) protein is thought to be the major mediator of cell cycle arrest after DNA damage. Previously p21 protein levels have been reported to increase or to decrease after UV irradiation. We show that p21 protein is degraded after irradiation of a variety of cell types with low but not high doses of UV. Cell cycle arrest occurs despite p21 degradation via Tyr(15) inhibitory phosphorylation of cdk2 and differs from the classical p21-dependent checkpoint elicited by ionizing radiation. In contrast to the basal turnover of p21, degradation of p21 switches to ubiquitin/Skp2-dependent proteasome pathway following UV irradiation. ATR activation after UV irradiation is essential for signaling p21 degradation. Finally, UV-induced p21 degradation is essential for optimal DNA repair. These results provide novel insight into regulation of p21 protein and its role in the cellular response to DNA damage.
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Checkpoint activation in XP-E or XP-C cells is intact.
“This is consistent with earlier studies showing that p21 degradation upon UV irradiation or low levels of p21 do not affect cell cycle checkpoint [57], and therefore we anticipate that checkpoint activation in XP-E or XP-C cells is intact.”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [57]
p21 is degraded upon lower doses of UV irradiation even though this lower level does not affect the cell cycle checkpoint.
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [57]
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Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840 · see citing works
Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control
Deng, C., Zhang, P., Wade Harper, J., Elledge, S. J., & Leder, P. (1995) · Cell · doi:10.1016/0092-8674(95)90039-x · Cited by 2,113 · see citing works
WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
El‐Deiry, W. S., Harper, J. W., O'Connor, P. M., Velculescu, V. E., Ce, C., Jackman, J., Pietenpol, J. A., Burrell, M., De, H., & Wang, Y. (1994) · PubMed · Cited by 2,021 · see citing works
The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA
Waga, S., Hannon, G. J., Beach, D., & Stillman, B. (1994) · Nature · doi:10.1038/369574a0 · Cited by 1,655 · see citing works
A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein
Chau, V., Tobias, J. W., Bachmair, A., Marriott, D., Ecker, D. J., Gonda, D. K., & Varshavsky, A. (1989) · Science · doi:10.1126/science.2538923 · Cited by 1,535 · see citing works
Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells
Stambolic, V., Ruel, L., & Woodgett, J. R. (1996) · Current Biology · doi:10.1016/s0960-9822(02)70790-2 · Cited by 1,321 · see citing works
Radiation-induced cell cycle arrest compromised by p21 deficiency
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J. (1995) · Nature · doi:10.1038/377552a0 · Cited by 1,242 · see citing works
Di Leonardo, A., Linke, S. P., Clarkin, K., & Wahl, G. M. (1994) · Genes & Development · doi:10.1101/gad.8.21.2540 · Cited by 1,215 · see citing works
p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage.Preprint
Macleod, K. F., Sherry, N., Hannon, G. J., Beach, D., Tokino, T., Kinzler, K. W., Vogelstein, B., & Jacks, T. (1995) · Genes & Development · doi:10.1101/gad.9.8.935 · Cited by 1,119 · see citing works
(1999) · PubMed · Cited by 1,030 · see citing works
Inhibition of cyclin-dependent kinases by p21.
Harper, J. W., Elledge, S. J., Keyomarsi, K., Dynlacht, B. D., Tsai, L., Zhang, P., Dobrowolski, S. F., Bai, C., Connell‐Crowley, L., & Swindell, E. C. (1995) · Molecular Biology of the Cell · doi:10.1091/mbc.6.4.387 · Cited by 1,025 · see citing works
ATR and ATRIP: Partners in Checkpoint Signaling
Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001) · Science · doi:10.1126/science.1065521 · Cited by 985 · see citing works
Mammalian DNA nucleotide excision repair reconstituted with purified protein components
Aboussekhra, A., Biggerstaff, M., Shivji, M. K. K., Vilpo, J. A., Moncollin, V., Podust, V. N., Protić, M., Hübscher, U., Egly, J.-M., & Wood, R. D. (1995) · Cell · doi:10.1016/0092-8674(95)90289-9 · Cited by 837 · see citing works
DNA repair: a laboratory manual of research procedures
(1981) · Annales de l Institut Pasteur Virologie · doi:10.1016/s0769-2617(81)80032-9 · Cited by 815 · see citing works
Proliferating cell nuclear antigen is required for DNA excision repair
Shivji, M. K. K., Kenny, M. K., & Wood, R. D. (1992) · Cell · doi:10.1016/0092-8674(92)90416-a · Cited by 803 · see citing works
Rapid Destruction of Human Cdc25A in Response to DNA Damage
Mailand, N., Falck, J., Lukas, C., Syljuåsen, R. G., Welcker, M., Bartek, J., & Lukas, J. (2000) · Science · doi:10.1126/science.288.5470.1425 · Cited by 787 · see citing works
Wood, R. D. (1996) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.65.070196.001031 · Cited by 678 · see citing works
Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair
Li, R., Waga, S., Hannon, G. J., Beach, D., & Stillman, B. (1994) · Nature · doi:10.1038/371534a0 · Cited by 645 · see citing works
Smith, M. L., Ford, J. M., Hollander, M. C., Bortnick, R. A., Amundson, S. A., Seo, Y. R., Deng, C., Hanawalt, P. C., & Fornace, A. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.10.3705-3714.2000 · Cited by 432 · see citing works
Proteasomal Turnover of p21Cip1 Does Not Require p21Cip1 Ubiquitination
Sheaff, R. J., Singer, J. D., Swanger, J., Smitherman, M., Roberts, J. M., & Clurman, B. E. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80435-9 · Cited by 382 · see citing works
Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes.
Zhang, H., Xiong, Y., & Beach, D. (1993) · Molecular Biology of the Cell · doi:10.1091/mbc.4.9.897 · Cited by 361 · see citing works
p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells
Cayrol, C., Knibiehler, M., & Ducommun, B. (1998) · Oncogene · doi:10.1038/sj.onc.1201543 · Cited by 338 · see citing works
Ubiquitination of p53 and p21 Is Differentially Affected by Ionizing and UV Radiation
Maki, C. G., & Howley, P. M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.355 · Cited by 305 · see citing works
Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts
Pagano, M., Theodoras, A. M., Tam, S. W., & Draetta, G. F. (1994) · Genes & Development · doi:10.1101/gad.8.14.1627 · Cited by 294 · see citing works
Accumulation of p53 in a Mutant Cell Line Defective in the Ubiquitin Pathway
Chowdary, D., Dermody, J. J., Jha, K. K., & Ozer, H. L. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1997 · Cited by 278 · see citing works
Changes in cyclin/proliferating cell nuclear antigen distribution during DNA repair synthesis.
Toschi, L., & Bravo, R. (1988) · The Journal of Cell Biology · doi:10.1083/jcb.107.5.1623 · Cited by 243 · see citing works
Purification of PCNA as a nucleotide excision repair protein
Nichols, A. F., & Sancar, A. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.10.2441 · Cited by 224 · see citing works
Proteasome-Dependent Regulation of p21WAF1/CIP1Expression
Blagosklonny, M. V., Wu, G. S., Ōmura, S., & El‐Deiry, W. S. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.1546 · Cited by 221 · see citing works
Wirbelauer, C., Sutterlüty, H., Blondel, M., Gstaiger, M., Peter, M., Reymond, F., & Krek, W. (2000) · The EMBO Journal · doi:10.1093/emboj/19.20.5362 · Cited by 172 · see citing works
Poon, R. Y. C., Jiang, W. B., Toyoshima, H., & Hunter, T. R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.13283 · Cited by 171 · see citing works
Celis, J. E., & Madsen, P. (1986) · FEBS Letters · doi:10.1016/0014-5793(86)81127-9 · Cited by 163 · see citing works
Inhibition of nucleotide excision repair by the cyclin-dependent kinase inhibitor p21
Pan, Z.-Q., Reardon, J. T., Li, L., Flores-Rozas, H., Legerski, R., Sancar, A., & Hurwitz, J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.37.22008 · Cited by 151 · see citing works
Cip1 inhibits DNA replication but not PCNA-dependent nucleotide excision—repair
Shivji, M. K. K., Grey, S. J., Strausfeld, U. P., Wood, R. D., & Blow, J. J. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00244-x · Cited by 149 · see citing works
Subcellular distribution of p21 and PCNA in normal and repair-deficient cells following DNA damage
Li, R., Hannon, G. J., Beach, D., & Stillman, B. (1996) · Current Biology · doi:10.1016/s0960-9822(02)00452-9 · Cited by 142 · see citing works
Podust, V. N., Podust, L. M., Goubin, F., Ducommun, B., & Huebscher, U. (1995) · Biochemistry · doi:10.1021/bi00027a039 · Cited by 124 · see citing works
Rousseau, D. L., Cannella, D., Boulaire, J., FITZGERALD, P. J., Fotedar, A., & Fotedar, R. (1999) · Oncogene · doi:10.1038/sj.onc.1202681 · Cited by 117 · see citing works
Self-citationAccumulation of p53 in a Mutant Cell Line Defective in the Ubiquitin Pathway
Chowdary, D., Dermody, J. J., Jha, K. K., et al. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1997-2003.1994 · Cited by 92 · see citing works
Fotedar, R., FITZGERALD, P. J., Rousselle, T., Cannella, D., Dorée, M., Messier, H., & Fotedar, A. (1996) · PubMed · Cited by 89 · see citing works
Self-citationAllan, L. A., & Fried, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202931 · Cited by 83 · see citing works
Rousseau, D. L., Cannella, D., Boulaire, J., FITZGERALD, P. J., Fotedar, A., & Fotedar, R. (1999) · Oncogene · doi:10.1038/sj.onc.1202686 · Cited by 83 · see citing works
Self-citationThe C-terminal domain of p21 inhibits nucleotide excision repair In vitro and In vivo
Cooper, M. P., Balajee, A. S., & Bohr, V. A. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.7.2119 · Cited by 80 · see citing works
Detection of Nucleotide Excision Repair Incisions in Human Fibroblasts by Immunostaining for PCNA
Aboussekhra, A., & Wood, R. D. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1382 · Cited by 78 · see citing works
Resistance of human nucleotide excision repair synthesis in vitro to p21Cdn1
Shivji, M. K., Ferrari, E., Ball, K., Hübscher, U., & Wood, R. D. (1998) · Oncogene · doi:10.1038/sj.onc.1202352 · Cited by 72 · see citing works
Adimoolam, S., Lin, C., & Ford, J. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102240200 · Cited by 71 · see citing works
Lü, X., Burbidge, S. A., Griffin, S., et al. (1996) · PubMed · Cited by 67 · see citing works
The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis
Schoenfeld, A. R., Parris, T., Eisenberger, A. B., Davidowitz, E. J., Leon, M. D., Talasazan, F., Devarajan, P., & Burk, R. D. (2000) · Oncogene · doi:10.1038/sj.onc.1203985 · Cited by 57 · see citing works
Uncoupling of p21WAF1/CIP1/SDI1 mRNA and protein expression upon genotoxic stress
Butz, K., Geisen, C., Ullmann, A., Zentgraf, H., & Hoppe‐Seyler, F. (1998) · Oncogene · doi:10.1038/sj.onc.1201995 · Cited by 47 · see citing works
Role and regulation of p53 during an ultraviolet radiation-induced G1 cell cycle arrest.
Geyer, R. K., Nagasawa, H., Little, J. B., & Maki, C. G. (2000) · PubMed · Cited by 45 · see citing works
Wang, J. (1999) · International Journal of Radiation Biology · doi:10.1080/095530099140483 · Cited by 42 · see citing works
Nitrate, nitrite and N‐nitroso compounds in human bladder cancer associated with schistosomiasis
Badawi, A. F. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000515)86:4 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
TP53 gain-of-function mutation promotes inflammation in glioblastoma
Ham, S. W., Jeon, H.-Y., Jin, X., Kim, E.-J., Kim, J.-K., Shin, Y. J., Lee, Y., Kim, S. H., Lee, S. Y., Seo, S., et al. (2019) · Cell Death & Differentiation · doi:10.1038/s41418-018-0126-3 · Cited by 213 · see citing works
Regulation of p21WAF1/CIP1 Stability by WISp39, a Hsp90 Binding TPR Protein
Jascur, T., Brickner, H., Salles-Passador, I., Barbier, V., El Khissiin, A., Smith, B., Fotedar, R., & Fotedar, A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.11.049 · Cited by 145 · see citing works
Self-citationCDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
Mansilla, S. F., De La Vega, M. B., Calzetta, N. L., Siri, S. O., & Gottifredi, V. (2020) · Genes · doi:10.3390/genes11060593 · Cited by 114 · see citing works
The human Rad9–Rad1–Hus1 checkpoint complex stimulates flap endonuclease 1
Wang, W., Brandt, P., Rossi, M. L., Lindsey-Boltz, L., Podust, V., Fanning, E., Sancar, A., & Bambara, R. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407686101 · Cited by 98 · see citing works
Soria, G., Speroni, J., Podhajcer, O. L., Prives, C., & Gottifredi, V. (2008) · Journal of Cell Science · doi:10.1242/jcs.027730 · Cited by 94 · see citing works
Ray, A., Milum, K., Battu, A., Wani, G., & Wani, A. A. (2013) · DNA Repair · doi:10.1016/j.dnarep.2013.01.003 · Cited by 85 · see citing works
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
BackgroundResultDecreased p21 levels are required for efficient restart of DNA synthesis after S phase block
Gottifredi, V., McKinney, K., Poyurovsky, M. V., & Prives, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310373200 · Cited by 76 · see citing works
Srinivas, H., Juroske, D. M., Kalyankrishna, S., Cody, D. D., Price, R. E., Xu, X.-C., Narayanan, R., Weigel, N. L., & Kurie, J. M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1054-1069.2005 · Cited by 68 · see citing works
Sequential replication-coupled destruction at G1/S ensures genome stability
Coleman, K. E., Grant, G. D., Haggerty, R. A., Brantley, K., Shibata, E., Workman, B. D., Dutta, A., Varma, D., Purvis, J. E., & Cook, J. G. (2015) · Genes & Development · doi:10.1101/gad.263731.115 · Cited by 51 · see citing works
UV-triggered p21 degradation facilitates damaged-DNA replication and preserves genomic stability
Mansilla, S. F., Soria, G., Vallerga, M. B., Habif, M., Martinez-Lopez, W., Prives, C., & Gottifredi, V. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt475 · Cited by 50 · see citing works
Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells
Stuart, S. A., & Wang, J. Y. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808810200 · Cited by 28 · see citing works
Al‐Khalaf, H. H., Hendrayani, S., & Aboussekhra, A. (2012) · Molecular Carcinogenesis · doi:10.1002/mc.20864 · Cited by 13 · see citing works
Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase
Ciznadija, D., Zhu, X.-H., & Koff, A. (2011) · Cell Cycle · doi:10.4161/cc.10.16.16725 · Cited by 11 · see citing works
- Authors
- Bendjennat, M., Boulaire, J., Jascur, T., Brickner, H., Barbier, V., Sarasin, A., Fotedar, A., & Fotedar, R.
- Affiliations
- Institut de Biologie Structurale (FR)
- Sidney Kimmel Cancer Center (US)
- Institut Gustave Roussy (FR)
- Corresponding author
- Fotedar, Arun
- Fotedar, Rati
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 114
- Issue
- 5
- Pages
- 599-610
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1976544913
- Cited by
- 248
- References
- 51
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 4 · 2014: 13 · 2013: 19 · 2012: 11
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3607 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University (HCT116)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health (5r01ca074435-05)
- National Cancer Institute (CA74435, CA92321, R01CA092321)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p21, UV irradiation, ubiquitin-mediated proteolysis, Skp2, proteasome, DNA repair, ATR signaling, cell cycle arrest, DNA damage response, p53
- MeSH terms
- Animals, Caffeine, Cell Cycle, Cycloheximide, Detergents, DNA Damage, DNA Repair, Dose-Response Relationship, Drug, HeLa Cells, Humans, Microscopy, Fluorescence, Models, Biological, Phosphorylation, Precipitin Tests, Protein Synthesis Inhibitors, Temperature, Time Factors, Transfection, Tyrosine, Ultraviolet Rays, Signal Transduction, Cyclins, 3T3 Cells, Octoxynol, Cell Cycle Proteins, Ubiquitin, S-Phase Kinase-Associated Proteins, Cyclin-Dependent Kinase Inhibitor p21, Mice
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