Abstract
The tumor suppressor p53 plays a central role in stress responses and tumor suppression. The increasingly complex p53 network is controlled by multiple layers of mechanisms, including the genetic level, transcriptional level, and protein level. Post-translational modifications (PTMs) of p53 represent a precise and efficient form of regulation. To date, the modification of p53 by ubiquitin and ubiquitin-like proteins (UBLs) has been studied extensively, including SUMOylation, NEDDylation, FATylation, ISGylation, and the recently identified UFMylation. They affect p53 stability, conformation, localization, transcriptional activity and binding partners. Here, we review these recent discoveries and summarize our understanding of ubiquitination and UBL modifications of p53 to better comprehend the complex landscape of p53 regulation. We will discuss how the ubiquitination and UBL modifications of p53 dynamically adjust its function to respond to various stress stimuli, thereby determining cell fate.
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06 April 2022
A Correction to this paper has been published: https://doi.org/10.1007/s42764-022-00071-4
References
Abida, W. M., Nikolaev, A., Zhao, W., Zhang, W., & Gu, W. (2007). FBXO11 promotes the neddylation of p53 and inhibits its transcriptional activity. Journal of Biological Chemistry, 282(3), 1797–1804. https://doi.org/10.1074/jbc.M609001200
Aichem, A., Kalveram, B., Spinnenhirn, V., Kluge, K., Catone, N., Johansen, T., & Groettrup, M. (2012). The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation. Journal of Cell Science, 125(Pt 19), 4576–4585. https://doi.org/10.1242/jcs.107789
Ashikari, D., Takayama, K., Tanaka, T., Suzuki, Y., Obinata, D., Fujimura, T., Urano, T., Takahashi, S., & Inoue, S. Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer. Oncogene, 36(45), 6272–6281. https://doi.org/10.1038/onc.2017.225
Becker, J., Barysch, S. V., Karaca, S., Dittner, C., Hsiao, H. H., Berriel Diaz, M., Herzig, S., Urlaub, H., & Melchior, F. (2013). Detecting endogenous SUMO targets in mammalian cells and tissues. Nature Structural & Molecular Biology, 20(4), 525–531. https://doi.org/10.1038/nsmb.2526
Brandl, A., Wagner, T., Uhlig, K. M., Knauer, S. K., Stauber, R. H., Melchior, F., Schneider, G., Heinzel, T., & Kramer, O. H. (2012). Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress. Journal of Molecular Cell Biology, 4(5), 284–293. https://doi.org/10.1093/jmcb/mjs013
Bravo-Navas, S., Yanez, L., Romon, I., Briz, M., Dominguez-Garcia, J. J., & Pipaon, C. (2021). Map of ubiquitin-like post-translational modifications in chronic lymphocytic leukemia. Role of p53 lysine 120 NEDDylation. Leukemia, 35(12), 3568–3572. https://doi.org/10.1038/s41375-021-01184-7
Brown, J. P., Wei, W., & Sedivy, J. M. (1997). Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science, 277(5327), 831–834. https://doi.org/10.1126/science.277.5327.831
Cai, Y., Pi, W., Sivaprakasam, S., Zhu, X., Zhang, M., Chen, J., Makala, L., Lu, C., Wu, J., Teng, Y., Pace, B., Tuan, D., Singh, N., & Li, H. (2015). UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. PLoS Genetics, 11(11), e1005643. https://doi.org/10.1371/journal.pgen.1005643
Cai, Y., Zhu, G., Liu, S., Pan, Z., Quintero, M., Poole, C. J., Lu, C., Zhu, H., Islam, B., Riggelen, J. V., Browning, D., Liu, K., Blumberg, R., Singh, N., & Li, H. (2019). Indispensable role of the Ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation. Cell Discov, 5, 7. https://doi.org/10.1038/s41421-018-0070-x
Carr, S. M., Munro, S., & La Thangue, N. B. (2012). Lysine methylation and the regulation of p53. Essays in Biochemistry, 52, 79–92. https://doi.org/10.1042/bse0520079
Carter, S., Bischof, O., Dejean, A., & Vousden, K. H. (2007). C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nature Cell Biology, 9(4), 428–435. https://doi.org/10.1038/ncb1562
Chairatvit, K., Wongnoppavich, A., & Choonate, S. (2012). Up-regulation of interferon-stimulated gene15 and its conjugates by tumor necrosis factor-alpha via type I interferon-dependent and -independent pathways. Molecular and Cellular Biochemistry, 368(1–2), 195–201. https://doi.org/10.1007/s11010-012-1360-5
Chang, P. C., Izumiya, Y., Wu, C. Y., Fitzgerald, L. D., Campbell, M., Ellison, T. J., Lam, K. S., Luciw, P. A., & Kung, H. J. (2010). Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific. Journal of Biological Chemistry, 285(8), 5266–5273. https://doi.org/10.1074/jbc.M109.088088
Chao, C., Saito, S., Anderson, C. W., Appella, E., & Xu, Y. (2000). Phosphorylation of murine p53 at ser-18 regulates the p53 responses to DNA damage. Proceedings of the National Academy of Sciences of the United States of America, 97(22), 11936–11941. https://doi.org/10.1073/pnas.220252297
Chauhan, K. M., Chen, Y., Liu, A. T., Sun, X. X., & Dai, M. S. (2021). The SUMO-specific protease SENP1 deSUMOylates p53 and regulates its activity. Journal of Cellular Biochemistry, 122(2), 189–197. https://doi.org/10.1002/jcb.29838
Chen, L., & Chen, J. (2003). MDM2-ARF complex regulates p53 sumoylation. Oncogene, 22(34), 5348–5357. https://doi.org/10.1038/sj.onc.1206851
Chen, L., Gilkes, D. M., Pan, Y., Lane, W. S., & Chen, J. (2005). ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO Journal, 24(19), 3411–3422. https://doi.org/10.1038/sj.emboj.7600812
Chen, L., Li, Z., Zwolinska, A. K., Smith, M. A., Cross, B., Koomen, J., Yuan, Z. M., Jenuwein, T., Marine, J. C., Wright, K. L., & Chen, J. (2010). MDM2 recruitment of lysine methyltransferases regulates p53 transcriptional output. EMBO Journal, 29(15), 2538–2552. https://doi.org/10.1038/emboj.2010.140
Chen, Y. C., Chan, J. Y., Chiu, Y. L., Liu, S. T., Lozano, G., Wang, S. L., Ho, C. L., & Huang, S. M. (2013). Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis. Cell Death and Differentiation, 20(5), 732–743. https://doi.org/10.1038/cdd.2013.1
Chen, Y., Wang, Y. G., Li, Y., Sun, X. X., & Dai, M. S. (2017). Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget, 8(7), 11053–11062. https://doi.org/10.18632/oncotarget.14278
Chen, Z., Zhang, W., Yun, Z., Zhang, X., Gong, F., Wang, Y., Ji, S., & Leng, L. (2018). Ubiquitinlike protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen. Molecular Medicine Reports, 17(6), 7487–7496. https://doi.org/10.3892/mmr.2018.8843
Chipuk, J. E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D. D., & Green, D. R. (2005). PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science, 309(5741), 1732–1735. https://doi.org/10.1126/science.1114297
Chiu, Y. H., Sun, Q., & Chen, Z. J. (2007). E1–L2 activates both ubiquitin and FAT10. Molecular Cell, 27(6), 1014–1023. https://doi.org/10.1016/j.molcel.2007.08.020
Cho, J., Park, J., Shin, S. C., Jang, M., Kim, J. H., Kim, E. E., & Song, E. J. (2020). USP47 promotes tumorigenesis by negative regulation of p53 through deubiquitinating ribosomal protein S2. Cancers (basel). https://doi.org/10.3390/cancers12051137
Choi, Y., Kim, J. K., & Yoo, J. Y. (2014). NFkappaB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Molecular Oncology, 8(3), 642–655. https://doi.org/10.1016/j.molonc.2014.01.007
Chu, Y., & Yang, X. (2011). SUMO E3 ligase activity of TRIM proteins. Oncogene, 30(9), 1108–1116. https://doi.org/10.1038/onc.2010.462
Chuikov, S., Kurash, J. K., Wilson, J. R., Xiao, B., Justin, N., Ivanov, G. S., McKinney, K., Tempst, P., Prives, C., Gamblin, S. J., Barlev, N. A., & Reinberg, D. (2004). Regulation of p53 activity through lysine methylation. Nature, 432(7015), 353–360. https://doi.org/10.1038/nature03117
Cummins, J. M., Rago, C., Kohli, M., Kinzler, K. W., Lengauer, C., & Vogelstein, B. (2004). Tumour suppression: Disruption of HAUSP gene stabilizes p53. Nature, 428(6982), 1–486. https://doi.org/10.1038/nature02501
Dai, C., & Gu, W. (2010). p53 post-translational modification: Deregulated in tumorigenesis. Trends in Molecular Medicine, 16(11), 528–536. https://doi.org/10.1016/j.molmed.2010.09.002
Montes de Oca Luna, R., Wagner, D. S., & Lozano, G. (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature, 378(6553), 203–206. https://doi.org/10.1038/378203a0
Dohmesen, C., Koeppel, M., & Dobbelstein, M. (2008). Specific inhibition of Mdm2-mediated neddylation by Tip60. Cell Cycle, 7(2), 222–231. https://doi.org/10.4161/cc.7.2.5185
Dolgin, E. (2017). The most popular genes in the human genome. Nature, 551(7681), 427–431. https://doi.org/10.1038/d41586-017-07291-9
Dornan, D., Wertz, I., Shimizu, H., Arnott, D., Frantz, G. D., Dowd, P., O'Rourke, K., Koeppen, H., & Dixit, V. M. (2004). The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature, 429(6987), 86–92. https://doi.org/10.1038/nature02514
Doyle, S., Vaidya, S., O'Connell, R., Dadgostar, H., Dempsey, P., Wu, T., Rao, G., Sun, R., Haberland, M., Modlin, R., & Cheng, G. (2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity, 17(3), 251–263. https://doi.org/10.1016/s1074-7613(02)00390-4
Durfee, L. A., Lyon, N., Seo, K., & Huibregtse, J. M. (2010). The ISG15 conjugation system broadly targets newly synthesized proteins: Implications for the antiviral function of ISG15. Molecular Cell, 38(5), 722–732. https://doi.org/10.1016/j.molcel.2010.05.002
Enchev, R. I., Schulman, B. A., & Peter, M. (2015). Protein neddylation: Beyond cullin-RING ligases. Nature Reviews Molecular Cell Biology, 16(1), 30–44. https://doi.org/10.1038/nrm3919
Esser, C., Scheffner, M., & Hohfeld, J. (2005). The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. Journal of Biological Chemistry, 280(29), 27443–27448. https://doi.org/10.1074/jbc.M501574200
Fan, W., Cai, W., Parimoo, S., Schwarz, D. C., Lennon, G. G., & Weissman, S. M. (1996). Identification of seven new human MHC class I region genes around the HLA-F locus. Immunogenetics, 44(2), 97–103. https://doi.org/10.1007/BF02660056
Fu, S., Shao, S., Wang, L., Liu, H., Hou, H., Wang, Y., Wang, H., Huang, X., & Lv, R. (2017). USP3 stabilizes p53 protein through its deubiquitinase activity. Biochemical and Biophysical Research Communications, 492(2), 178–183. https://doi.org/10.1016/j.bbrc.2017.08.036
Fu, X., Wu, S., Li, B., Xu, Y., & Liu, J. (2020). Functions of p53 in pluripotent stem cells. Protein & Cell, 11(1), 71–78. https://doi.org/10.1007/s13238-019-00665-x
Gannon, H. S., Woda, B. A., & Jones, S. N. (2012). ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice. Cancer Cell, 21(5), 668–679. https://doi.org/10.1016/j.ccr.2012.04.011
Gavin, J. M., Chen, J. J., Liao, H., Rollins, N., Yang, X., Xu, Q., Ma, J., Loke, H. K., Lingaraj, T., Brownell, J. E., Mallender, W. D., Gould, A. E., Amidon, B. S., & Dick, L. R. (2012). Mechanistic studies on activation of ubiquitin and di-ubiquitin-like protein, FAT10, by ubiquitin-like modifier activating enzyme 6, Uba6. Journal of Biological Chemistry, 287(19), 15512–15522. https://doi.org/10.1074/jbc.M111.336198
Geiss-Friedlander, R., & Melchior, F. (2007). Concepts in sumoylation: A decade on. Nature Reviews Molecular Cell Biology, 8(12), 947–956. https://doi.org/10.1038/nrm2293
Gerakis, Y., Quintero, M., Li, H., & Hetz, C. (2019). The UFMylation system in proteostasis and beyond. Trends in Cell Biology, 29(12), 974–986. https://doi.org/10.1016/j.tcb.2019.09.005
Glickman, M. H., & Ciechanover, A. (2002). The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiological Reviews, 82(2), 373–428. https://doi.org/10.1152/physrev.00027.2001
Gostissa, M., Hengstermann, A., Fogal, V., Sandy, P., Schwarz, S. E., Scheffner, M., & Del Sal, G. (1999). Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO Journal, 18(22), 6462–6471. https://doi.org/10.1093/emboj/18.22.6462
Grossman, S. R., Deato, M. E., Brignone, C., Chan, H. M., Kung, A. L., Tagami, H., Nakatani, Y., & Livingston, D. M. (2003). Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science, 300(5617), 342–344. https://doi.org/10.1126/science.1080386
Gu, B., & Zhu, W. G. (2012). Surf the post-translational modification network of p53 regulation. International Journal of Biological Sciences, 8(5), 672–684. https://doi.org/10.7150/ijbs.4283
Gu, W., & Roeder, R. G. (1997). Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell, 90(4), 595–606. https://doi.org/10.1016/s0092-8674(00)80521-8
Guo, H., Shen, S., Li, Y., Bi, R., Zhang, N., Zheng, W., Deng, Y., Yang, Y., Yu, X. F., Wang, C., & Wei, W. (2019). Adenovirus oncoprotein E4orf6 triggers Cullin5 neddylation to activate the CLR5 E3 ligase for p53 degradation. Biochemical and Biophysical Research Communications, 516(4), 1242–1247. https://doi.org/10.1016/j.bbrc.2019.07.028
Haas, A. L., Ahrens, P., Bright, P. M., & Ankel, H. (1987). Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. Journal of Biological Chemistry, 262(23), 11315–11323.
Hakem, A., Bohgaki, M., Lemmers, B., Tai, E., Salmena, L., Matysiak-Zablocki, E., Jung, Y. S., Karaskova, J., Kaustov, L., Duan, S., Madore, J., Boutros, P., Sheng, Y., Chesi, M., Bergsagel, P. L., Perez-Ordonez, B., Mes-Masson, A. M., Penn, L., Squire, J., Chen, X., Jurisica, I., Arrowsmith, C., Sanchez, O., Benchimol, S., & Hakem, R. (2011). Role of Pirh2 in mediating the regulation of p53 and c-Myc. PLoS Genetics, 7(11), e1002360. https://doi.org/10.1371/journal.pgen.1002360
Hauck, P. M., Wolf, E. R., Olivos, D. J., 3rd, McAtarsney, C. P., & Mayo, L. D. (2017). The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2). Oncotarget, 8(61), 104455–104466. https://doi.org/10.18632/oncotarget.22320
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997). Mdm2 promotes the rapid degradation of p53. Nature, 387(6630), 296–299. https://doi.org/10.1038/387296a0
Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P., & Dikic, I. (2006). Specification of SUMO1- and SUMO2-interacting motifs. Journal of Biological Chemistry, 281(23), 16117–16127. https://doi.org/10.1074/jbc.M512757200
Hendriks, I. A., D’Souza, R. C., Yang, B., Verlaan-de Vries, M., Mann, M., & Vertegaal, A. C. (2014). Uncovering global SUMOylation signaling networks in a site-specific manner. Nature Structural & Molecular Biology, 21(10), 927–936. https://doi.org/10.1038/nsmb.2890
Hock, A. K., Vigneron, A. M., Carter, S., Ludwig, R. L., & Vousden, K. H. (2011). Regulation of p53 stability and function by the deubiquitinating enzyme USP42. EMBO Journal, 30(24), 4921–4930. https://doi.org/10.1038/emboj.2011.419
Honda, R., Tanaka, H., & Yasuda, H. (1997). Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Letters, 420(1), 25–27. https://doi.org/10.1016/s0014-5793(97)01480-4
Hu, W., Feng, Z., & Levine, A. J. (2012). The regulation of multiple p53 stress responses is mediated through MDM2. Genes & Cancer, 3(3–4), 199–208. https://doi.org/10.1177/1947601912454734
Huang, Y. F., & Bulavin, D. V. (2014). Oncogene-mediated regulation of p53 ISGylation and functions. Oncotarget, 5(14), 5808–5818. https://doi.org/10.18632/oncotarget.2199
Huang, Y. F., Wee, S., Gunaratne, J., Lane, D. P., & Bulavin, D. V. (2014). Isg15 controls p53 stability and functions. Cell Cycle, 13(14), 2200–2210. https://doi.org/10.4161/cc.29209
Ito, A., Kawaguchi, Y., Lai, C. H., Kovacs, J. J., Higashimoto, Y., Appella, E., & Yao, T. P. (2002). MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO Journal, 21(22), 6236–6245. https://doi.org/10.1093/emboj/cdf616
Ito, A., Lai, C. H., Zhao, X., Saito, S., Hamilton, M. H., Appella, E., & Yao, T. P. (2001). p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO Journal, 20(6), 1331–1340. https://doi.org/10.1093/emboj/20.6.1331
Jeram, S. M., Srikumar, T., Zhang, X. D., Anne Eisenhauer, H., Rogers, R., Pedrioli, P. G., Matunis, M., & Raught, B. (2010). An improved SUMmOn-based methodology for the identification of ubiquitin and ubiquitin-like protein conjugation sites identifies novel ubiquitin-like protein chain linkages. Proteomics, 10(2), 254–265. https://doi.org/10.1002/pmic.200900648
Jiang, L., Kon, N., Li, T., Wang, S. J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015). Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 520(7545), 57–62. https://doi.org/10.1038/nature14344
Jiang, M., Chiu, S. Y., & Hsu, W. (2011). SUMO-specific protease 2 in Mdm2-mediated regulation of p53. Cell Death and Differentiation, 18(6), 1005–1015. https://doi.org/10.1038/cdd.2010.168
Jin, J., Li, X., Gygi, S. P., & Harper, J. W. (2007). Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature, 447(7148), 1135–1138. https://doi.org/10.1038/nature05902
Jones, J., Wu, K., Yang, Y., Guerrero, C., Nillegoda, N., Pan, Z. Q., & Huang, L. (2008). A targeted proteomic analysis of the ubiquitin-like modifier nedd8 and associated proteins. Journal of Proteome Research, 7(3), 1274–1287. https://doi.org/10.1021/pr700749v
Jones, S. N., Hancock, A. R., Vogel, H., Donehower, L. A., & Bradley, A. (1998). Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci U S A, 95(26), 15608–15612. https://doi.org/10.1073/pnas.95.26.15608
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature, 378(6553), 206–208. https://doi.org/10.1038/378206a0
Ka, W. H., Cho, S. K., Chun, B. N., Byun, S. Y., & Ahn, J. C. (2018). The ubiquitin ligase COP1 regulates cell cycle and apoptosis by affecting p53 function in human breast cancer cell lines. Breast Cancer, 25(5), 529–538. https://doi.org/10.1007/s12282-018-0849-5
Kahyo, T., Nishida, T., & Yasuda, H. (2001). Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Molecular Cell, 8(3), 713–718. https://doi.org/10.1016/s1097-2765(01)00349-5
Kastenhuber, E. R., & Lowe, S. W. (2017). Putting p53 in context. Cell, 170(6), 1062–1078. https://doi.org/10.1016/j.cell.2017.08.028
Kim, K. I., Giannakopoulos, N. V., Virgin, H. W., & Zhang, D. E. (2004). Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation. Molecular and Cellular Biology, 24(21), 9592–9600. https://doi.org/10.1128/MCB.24.21.9592-9600.2004
Ko, L. J., & Prives, C. (1996). p53: Puzzle and paradigm. Genes & Development, 10(9), 1054–1072. https://doi.org/10.1101/gad.10.9.1054
Komander, D. (2009). The emerging complexity of protein ubiquitination. Biochemical Society Transactions, 37(Pt 5), 937–953. https://doi.org/10.1042/BST0370937
Komatsu, M., Chiba, T., Tatsumi, K., Iemura, S., Tanida, I., Okazaki, N., Ueno, T., Kominami, E., Natsume, T., & Tanaka, K. (2004). A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. EMBO Journal, 23(9), 1977–1986. https://doi.org/10.1038/sj.emboj.7600205
Krug, R. M., Zhao, C., & Beaudenon, S. (2005). Properties of the ISG15 E1 enzyme UbE1L. Methods in Enzymology, 398, 32–40. https://doi.org/10.1016/S0076-6879(05)98004-X
Kruse, J. P., & Gu, W. (2008). SnapShot: p53 posttranslational modifications. Cell, 133(5), 930-930.e931. https://doi.org/10.1016/j.cell.2008.05.020
Kruse, J. P., & Gu, W. (2009a). Modes of p53 regulation. Cell, 137(4), 609–622. https://doi.org/10.1016/j.cell.2009.04.050
Kruse, J. P., & Gu, W. (2009b). MSL2 promotes Mdm2-independent cytoplasmic localization of p53. Journal of Biological Chemistry, 284(5), 3250–3263. https://doi.org/10.1074/jbc.M805658200
Kubbutat, M. H., Jones, S. N., & Vousden, K. H. (1997). Regulation of p53 stability by Mdm2. Nature, 387(6630), 299–303. https://doi.org/10.1038/387299a0
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996). Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science, 274(5289), 948–953. https://doi.org/10.1126/science.274.5289.948
Kwek, S. S., Derry, J., Tyner, A. L., Shen, Z., & Gudkov, A. V. (2001). Functional analysis and intracellular localization of p53 modified by SUMO-1. Oncogene, 20(20), 2587–2599. https://doi.org/10.1038/sj.onc.1204362
Kwon, S. K., Saindane, M., & Baek, K. H. (2017). p53 stability is regulated by diverse deubiquitinating enzymes. Biochimica Et Biophysica Acta - Reviews on Cancer, 1868(2), 404–411. https://doi.org/10.1016/j.bbcan.2017.08.001
Kwon, Y. T., & Ciechanover, A. (2017). The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends in Biochemical Sciences, 42(11), 873–886. https://doi.org/10.1016/j.tibs.2017.09.002
Lahav-Baratz, S., Kravtsova-Ivantsiv, Y., Golan, S., & Ciechanover, A. (2017). The testis-specific USP26 is a deubiquitinating enzyme of the ubiquitin ligase Mdm2. Biochemical and Biophysical Research Communications, 482(1), 106–111. https://doi.org/10.1016/j.bbrc.2016.10.135
Laine, A., & Ronai, Z. (2007). Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene, 26(10), 1477–1483. https://doi.org/10.1038/sj.onc.1209924
Lane, D. P. (1992). Cancer.p53, guardian of the genome. Nature, 358(6381), 15–16. https://doi.org/10.1038/358015a0
Le Cam, L., Linares, L. K., Paul, C., Julien, E., Lacroix, M., Hatchi, E., Triboulet, R., Bossis, G., Shmueli, A., Rodriguez, M. S., Coux, O., & Sardet, C. (2006). E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell, 127(4), 775–788. https://doi.org/10.1016/j.cell.2006.09.031
Lee, E. W., Lee, M. S., Camus, S., Ghim, J., Yang, M. R., Oh, W., Ha, N. C., Lane, D. P., & Song, J. (2009). Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. EMBO Journal, 28(14), 2100–2113. https://doi.org/10.1038/emboj.2009.164
Lee, L., Perez Oliva, A. B., Martinez-Balsalobre, E., Churikov, D., Peter, J., Rahmouni, D., Audoly, G., Azzoni, V., Audebert, S., Camoin, L., Mulero, V., Cayuela, M. L., Kulathu, Y., Geli, V., & Lachaud, C. (2021). UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival. Science Advances, 7(39), eabc7371. https://doi.org/10.1126/sciadv.abc7371
Leidecker, O., Matic, I., Mahata, B., Pion, E., & Xirodimas, D. P. (2012). The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions. Cell Cycle, 11(6), 1142–1150. https://doi.org/10.4161/cc.11.6.19559
Lemaire, K., Moura, R. F., Granvik, M., Igoillo-Esteve, M., Hohmeier, H. E., Hendrickx, N., Newgard, C. B., Waelkens, E., Cnop, M., & Schuit, F. (2011). Ubiquitin fold modifier 1 (UFM1) and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis. PLoS ONE, 6(4), e18517. https://doi.org/10.1371/journal.pone.0018517
Leng, L., Xu, C., Wei, C., Zhang, J., Liu, B., Ma, J., Li, N., Qin, W., Zhang, W., Zhang, C., Xing, X., Zhai, L., Yang, F., Li, M., Jin, C., Yuan, Y., Xu, P., Qin, J., Xie, H., He, F., & Wang, J. (2014). A proteomics strategy for the identification of FAT10-modified sites by mass spectrometry. Journal of Proteome Research, 13(1), 268–276. https://doi.org/10.1021/pr400395k
Leng, R. P., Lin, Y., Ma, W., Wu, H., Lemmers, B., Chung, S., Parant, J. M., Lozano, G., Hakem, R., & Benchimol, S. (2003). Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell, 112(6), 779–791. https://doi.org/10.1016/s0092-8674(03)00193-4
Li, F., Han, H., Sun, Q., Liu, K., Lin, N., Xu, C., Zhao, Z., & Zhao, W. (2019). USP28 regulates deubiquitination of histone H2A and cell proliferation. Experimental Cell Research, 379(1), 11–18. https://doi.org/10.1016/j.yexcr.2019.03.026
Li, J., Lu, D., Dou, H., Liu, H., Weaver, K., Wang, W., Yeh, E. T. H., Williams, B. O., Zheng, L., & Yang, T. (2018). Desumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway. Nature Communications, 9(1), 143. https://doi.org/10.1038/s41467-017-02413-3
Li, J., Yue, G., Ma, W., Zhang, A., Zou, J., Cai, Y., Tang, X., Wang, J., Liu, J., Li, H., & Su, H. (2018). Ufm1-specific ligase Ufl1 regulates endoplasmic reticulum homeostasis and protects against heart failure. Circulation. Heart Failure, 11(10), e004917. https://doi.org/10.1161/CIRCHEARTFAILURE.118.004917
Li, M., Brooks, C. L., Kon, N., & Gu, W. (2004). A dynamic role of HAUSP in the p53-Mdm2 pathway. Molecular Cell, 13(6), 879–886. https://doi.org/10.1016/s1097-2765(04)00157-1
Li, M., Brooks, C. L., Wu-Baer, F., Chen, D., Baer, R., & Gu, W. (2003). Mono- versus polyubiquitination: Differential control of p53 fate by Mdm2. Science, 302(5652), 1972–1975. https://doi.org/10.1126/science.1091362
Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J., & Gu, W. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature, 416(6881), 648–653. https://doi.org/10.1038/nature737
Li, M., Luo, J., Brooks, C. L., & Gu, W. (2002). Acetylation of p53 inhibits its ubiquitination by Mdm2. Journal of Biological Chemistry, 277(52), 50607–50611. https://doi.org/10.1074/jbc.C200578200
Li, Q., Lin, S., Wang, X., Lian, G., Lu, Z., Guo, H., Ruan, K., Wang, Y., Ye, Z., Han, J., & Lin, S. C. (2009). Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nature Cell Biology, 11(9), 1128–1134. https://doi.org/10.1038/ncb1927
Li, T., Santockyte, R., Shen, R. F., Tekle, E., Wang, G., Yang, D. C., & Chock, P. B. (2006). Expression of SUMO-2/3 induced senescence through p53- and pRB-mediated pathways. Journal of Biological Chemistry, 281(47), 36221–36227. https://doi.org/10.1074/jbc.M608236200
Li, T., Santockyte, R., Yu, S., Shen, R. F., Tekle, E., Lee, C. G., Yang, D. C., & Chock, P. B. (2011). FAT10 modifies p53 and upregulates its transcriptional activity. Archives of Biochemistry and Biophysics, 509(2), 164–169. https://doi.org/10.1016/j.abb.2011.02.017
Liang, J. R., Lingeman, E., Luong, T., Ahmed, S., Muhar, M., Nguyen, T., Olzmann, J. A., & Corn, J. E. (2020). A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation. Cell, 180(6), 1160-1177.e1120. https://doi.org/10.1016/j.cell.2020.02.017
Liao, P., Bhattarai, N., Cao, B., Zhou, X., Jung, J. H., Damera, K., Fuselier, T. T., Thareja, S., Wimley, W. C., Wang, B., Zeng, S. X., & Lu, H. (2020). Crotonylation at serine 46 impairs p53 activity. Biochemical and Biophysical Research Communications, 524(3), 730–735. https://doi.org/10.1016/j.bbrc.2020.01.152
Linares, L. K., Kiernan, R., Triboulet, R., Chable-Bessia, C., Latreille, D., Cuvier, O., Lacroix, M., Le Cam, L., Coux, O., & Benkirane, M. (2007). Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nature Cell Biology, 9(3), 331–338. https://doi.org/10.1038/ncb1545
Liu, C., Chang, R., Yao, X., Qiao, W. T., & Geng, Y. Q. (2009). ISG15 expression in response to double-stranded RNA or LPS in cultured fetal bovine lung (FBL) cells. Veterinary Research Communications, 33(7), 723–733. https://doi.org/10.1007/s11259-009-9221-8
Liu, F., Gao, X., Wang, J., Gao, C., Li, X., Gong, X., & Zeng, X. (2016). Transcriptome sequencing to identify transcription factor regulatory network and alternative splicing in endothelial cells under VEGF stimulation. Journal of Molecular Neuroscience, 58(2), 170–177. https://doi.org/10.1007/s12031-015-0653-z
Liu, G., & Xirodimas, D. P. (2010). NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways. Oncogene, 29(15), 2252–2261. https://doi.org/10.1038/onc.2009.494
Liu, H., Li, X., Ning, G., Zhu, S., Ma, X., Liu, X., Liu, C., Huang, M., Schmitt, I., Wullner, U., Niu, Y., Guo, C., Wang, Q., & Tang, T. S. (2016). The Machado-Joseph disease deubiquitinase ataxin-3 regulates the stability and apoptotic function of p53. PLoS Biology, 14(11), e2000733. https://doi.org/10.1371/journal.pbio.2000733
Liu, J., Guan, D., Dong, M., Yang, J., Wei, H., Liang, Q., Song, L., Xu, L., Bai, J., Liu, C., Mao, J., Zhang, Q., Zhou, J., Wu, X., Wang, M., & Cong, Y. S. (2020). UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature Cell Biology, 22(9), 1056–1063. https://doi.org/10.1038/s41556-020-0559-z
Liu, J., Wang, Y., Song, L., Zeng, L., Yi, W., Liu, T., Chen, H., Wang, M., Ju, Z., & Cong, Y. S. (2017). A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1alpha stability. Nature Communications, 8, 14186. https://doi.org/10.1038/ncomms14186
Liu, J., Zhang, C., Hu, W., & Feng, Z. (2019). Tumor suppressor p53 and metabolism. Journal of Molecular Cell Biology, 11(4), 284–292. https://doi.org/10.1093/jmcb/mjy070
Liu, X., Chen, L., Ge, J., Yan, C., Huang, Z., Hu, J., Wen, C., Li, M., Huang, D., Qiu, Y., Hao, H., Yuan, R., Lei, J., Yu, X., & Shao, J. (2016). The ubiquitin-like protein FAT10 stabilizes eEF1A1 expression to promote tumor proliferation in a complex manner. Cancer Research, 76(16), 4897–4907. https://doi.org/10.1158/0008-5472.CAN-15-3118
Liu, X., Tan, Y., Zhang, C., Zhang, Y., Zhang, L., Ren, P., Deng, H., Luo, J., Ke, Y., & Du, X. (2016). NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2. EMBO Reports, 17(3), 349–366
Liu, Y. C., Pan, J., Zhang, C., Fan, W., Collinge, M., Bender, J. R., & Weissman, S. M. (1999). A MHC-encoded ubiquitin-like protein (FAT10) binds noncovalently to the spindle assembly checkpoint protein MAD2. Proceedings of the National Academy of Sciences of the United States of America, 96(8), 4313–4318. https://doi.org/10.1073/pnas.96.8.4313
Liu, Y., Tavana, O., & Gu, W. (2019). p53 modifications: Exquisite decorations of the powerful guardian. Journal of Molecular Cell Biology, 11(7), 564–577. https://doi.org/10.1093/jmcb/mjz060
Lou, Z., Wei, J., Riethman, H., Baur, J. A., Voglauer, R., Shay, J. W., & Wright, W. E. (2009). Telomere length regulates ISG15 expression in human cells. Aging (albany NY), 1(7), 608–621. https://doi.org/10.18632/aging.100066
Luo, J., Lu, Z., Lu, X., Chen, L., Cao, J., Zhang, S., Ling, Y., & Zhou, X. (2013). OTUD5 regulates p53 stability by deubiquitinating p53. PLoS ONE, 8(10), e77682. https://doi.org/10.1371/journal.pone.0077682
Luo, J., Su, F., Chen, D., Shiloh, A., & Gu, W. (2000). Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature, 408(6810), 377–381. https://doi.org/10.1038/35042612
Marine, J. C., Dyer, M. A., & Jochemsen, A. G. (2007). MDMX: From bench to bedside. Journal of Cell Science, 120(Pt 3), 371–378. https://doi.org/10.1242/jcs.03362
Marx, J. (1993). How p53 suppresses cell growth. Science, 262(5140), 1644–1645. https://doi.org/10.1126/science.8259506
Maya, R., Balass, M., Kim, S. T., Shkedy, D., Leal, J. F., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., Kastan, M. B., Katzir, E., & Oren, M. (2001). ATM-dependent phosphorylation of Mdm2 on serine 395: Role in p53 activation by DNA damage. Genes & Development, 15(9), 1067–1077. https://doi.org/10.1101/gad.886901
Meek, D. W., & Anderson, C. W. (2009). Posttranslational modification of p53: Cooperative integrators of function. Cold Spring Harbor Perspectives in Biology, 1(6), a000950. https://doi.org/10.1101/cshperspect.a000950
Nakamura, S., Roth, J. A., & Mukhopadhyay, T. (2000). Multiple lysine mutations in the C-terminal domain of p53 interfere with MDM2-dependent protein degradation and ubiquitination. Molecular and Cellular Biology, 20(24), 9391–9398. https://doi.org/10.1128/MCB.20.24.9391-9398.2000
Nakashima, H., Nguyen, T., Goins, W. F., & Chiocca, E. A. (2015). Interferon-stimulated gene 15 (ISG15) and ISG15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (HDAC6) and SQSTM1/p62. Journal of Biological Chemistry, 290(3), 1485–1495. https://doi.org/10.1074/jbc.M114.593871
Nakka, V. P., Lang, B. T., Lenschow, D. J., Zhang, D. E., Dempsey, R. J., & Vemuganti, R. (2011). Increased cerebral protein ISGylation after focal ischemia is neuroprotective. Journal of Cerebral Blood Flow and Metabolism, 31(12), 2375–2384. https://doi.org/10.1038/jcbfm.2011.103
Nelson, V., Davis, G. E., & Maxwell, S. A. (2001). A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis. Apoptosis, 6(3), 221–234. https://doi.org/10.1023/a:1011392811628
Nie, Q., Chen, H., Zou, M., Wang, L., Hou, M., Xiang, J. W., Luo, Z., Gong, X. D., Fu, J. L., Wang, Y., Zheng, S. Y., Xiao, Y., Gan, Y. W., Gao, Q., Bai, Y. Y., Wang, J. M., Zhang, L., Tang, X. C., Hu, X., Gong, L., Liu, Y., & Li, D. W. (2021). The E3 ligase PIAS1 regulates p53 sumoylation to control stress-induced apoptosis of lens epithelial cells through the proapoptotic regulator bax. Front Cell Dev Biol, 9, 660494. https://doi.org/10.3389/fcell.2021.660494
Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, T., Tokino, T., Taniguchi, T., & Tanaka, N. (2000). Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science, 288(5468), 1053–1058. https://doi.org/10.1126/science.288.5468.1053
Ofir-Rosenfeld, Y., Boggs, K., Michael, D., Kastan, M. B., & Oren, M. (2008). Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Molecular Cell, 32(2), 180–189. https://doi.org/10.1016/j.molcel.2008.08.031
Okumura, F., Okumura, A. J., Uematsu, K., Hatakeyama, S., Zhang, D. E., & Kamura, T. (2013). Activation of double-stranded RNA-activated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation. Journal of Biological Chemistry, 288(4), 2839–2847. https://doi.org/10.1074/jbc.M112.401851
Owerbach, D., McKay, E. M., Yeh, E. T., Gabbay, K. H., & Bohren, K. M. (2005). A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochemical and Biophysical Research Communications, 337(2), 517–520. https://doi.org/10.1016/j.bbrc.2005.09.090
Pan, M., & Blattner, C. (2021). Regulation of p53 by E3s. Cancers (basel). https://doi.org/10.3390/cancers13040745
Park, J. H., Yang, S. W., Park, J. M., Ka, S. H., Kim, J. H., Kong, Y. Y., Jeon, Y. J., Seol, J. H., & Chung, C. H. (2016). Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification. Nature Communications, 7, 12513. https://doi.org/10.1038/ncomms12513
Park, S. Y., Phorl, S., Jung, S., Sovannarith, K., Lee, S. I., Noh, S., Han, M., Naskar, R., Kim, J. Y., Choi, Y. J., & Lee, J. Y. (2017). HDAC6 deficiency induces apoptosis in mesenchymal stem cells through p53 K120 acetylation. Biochemical and Biophysical Research Communications, 494(1–2), 51–56. https://doi.org/10.1016/j.bbrc.2017.10.087
Pearce, M. J., Mintseris, J., Ferreyra, J., Gygi, S. P., & Darwin, K. H. (2008). Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science, 322(5904), 1104–1107. https://doi.org/10.1126/science.1163885
Pennella, M. A., Liu, Y., Woo, J. L., Kim, C. A., & Berk, A. J. (2010). Adenovirus E1B 55-kilodalton protein is a p53-SUMO1 E3 ligase that represses p53 and stimulates its nuclear export through interactions with promyelocytic leukemia nuclear bodies. Journal of Virology, 84(23), 12210–12225. https://doi.org/10.1128/JVI.01442-10
Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F., Lehmann, W. D., Jochemsen, A. G., & Shiloh, Y. (2005). Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc Natl Acad Sci U S A, 102(14), 5056–5061. https://doi.org/10.1073/pnas.0408595102
Pitha-Rowe, I., Hassel, B. A., & Dmitrovsky, E. (2004). Involvement of UBE1L in ISG15 conjugation during retinoid-induced differentiation of acute promyelocytic leukemia. Journal of Biological Chemistry, 279(18), 18178–18187. https://doi.org/10.1074/jbc.M309259200
Qin, B., Yu, J., Nowsheen, S., Wang, M., Tu, X., Liu, T., Li, H., Wang, L., & Lou, Z. (2019). UFL1 promotes histone H4 ufmylation and ATM activation. Nature Communications, 10(1), 1242. https://doi.org/10.1038/s41467-019-09175-0
Qin, B., Yu, J., Nowsheen, S., Zhao, F., Wang, L., & Lou, Z. (2020). STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation. Science Advances, 6(23), eaxx8214. https://doi.org/10.1126/sciadv.aax8214
Rodriguez, M. S., Desterro, J. M., Lain, S., Lane, D. P., & Hay, R. T. (2000). Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Molecular and Cellular Biology, 20(22), 8458–8467. https://doi.org/10.1128/MCB.20.22.8458-8467.2000
Rodriguez, M. S., Desterro, J. M., Lain, S., Midgley, C. A., Lane, D. P., & Hay, R. T. (1999). SUMO-1 modification activates the transcriptional response of p53. EMBO Journal, 18(22), 6455–6461. https://doi.org/10.1093/emboj/18.22.6455
Rodriguez-Bravo, V., Maciejowski, J., Corona, J., Buch, H. K., Collin, P., Kanemaki, M. T., Shah, J. V., & Jallepalli, P. V. (2014). Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor. Cell, 156(5), 1017–1031. https://doi.org/10.1016/j.cell.2014.01.010
Russo, A., & Russo, G. (2017). Ribosomal Proteins Control or Bypass p53 during Nucleolar Stress. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms18010140
Ryan, S. D., Britigan, E. M., Zasadil, L. M., Witte, K., Audhya, A., Roopra, A., & Weaver, B. A. (2012). Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proceedings of the National Academy of Sciences of the United States of America, 109(33), E2205-2214. https://doi.org/10.1073/pnas.1201911109
Ryu, H. W., Shin, D. H., Lee, D. H., Choi, J., Han, G., Lee, K. Y., & Kwon, S. H. (2017). HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis. Cancer Letters, 391, 162–171. https://doi.org/10.1016/j.canlet.2017.01.033
Saadatzadeh, M. R., Elmi, A. N., Pandya, P. H., Bijangi-Vishehsaraei, K., Ding, J., Stamatkin, C. W., Cohen-Gadol, A. A., & Pollok, K. E. (2017). The role of MDM2 in promoting genome stability versus instability. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms18102216
Sadler, A. J., & Williams, B. R. (2008). Interferon-inducible antiviral effectors. Nature Reviews Immunology, 8(7), 559–568. https://doi.org/10.1038/nri2314
Saitoh, H., & Hinchey, J. (2000). Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. Journal of Biological Chemistry, 275(9), 6252–6258. https://doi.org/10.1074/jbc.275.9.6252
Sanford, J. D., Yang, J., Han, J., Tollini, L. A., Jin, A., & Zhang, Y. (2021). MDMX is essential for the regulation of p53 protein levels in the absence of a functional MDM2 C-terminal tail. BMC Mol Cell Biol, 22(1), 46. https://doi.org/10.1186/s12860-021-00385-3
Santonico, E. (2020). Old and new concepts in ubiquitin and NEDD8 recognition. Biomolecules. https://doi.org/10.3390/biom10040566
Scheffner, M., Huibregtse, J. M., Vierstra, R. D., & Howley, P. M. (1993). The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell, 75(3), 495–505. https://doi.org/10.1016/0092-8674(93)90384-3
Schmidt, D., & Muller, S. (2002). Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proceedings of the National Academy of Sciences of the United States of America, 99(5), 2872–2877. https://doi.org/10.1073/pnas.052559499
Schmidtke, G., Aichem, A., & Groettrup, M. (2014). FAT10ylation as a signal for proteasomal degradation. Biochimica Et Biophysica Acta, 1843(1), 97–102. https://doi.org/10.1016/j.bbamcr.2013.01.009
Sen, G. C., & Sarkar, S. N. (2007). The interferon-stimulated genes: Targets of direct signaling by interferons, double-stranded RNA, and viruses. Current Topics in Microbiology and Immunology, 316, 233–250. https://doi.org/10.1007/978-3-540-71329-6_12
Shen, J., Li, P., Shao, X., Yang, Y., Liu, X., Feng, M., Yu, Q., Hu, R., & Wang, Z. (2018). The E3 ligase RING1 targets p53 for degradation and promotes cancer cell proliferation and survival. Cancer Research, 78(2), 359–371. https://doi.org/10.1158/0008-5472.CAN-17-1805
Sheng, Y., Laister, R. C., Lemak, A., Wu, B., Tai, E., Duan, S., Lukin, J., Sunnerhagen, M., Srisailam, S., Karra, M., Benchimol, S., & Arrowsmith, C. H. (2008). Molecular basis of Pirh2-mediated p53 ubiquitylation. Nature Structural & Molecular Biology, 15(12), 1334–1342. https://doi.org/10.1038/nsmb.1521
Sheren, J. E., & Kassenbrock, C. K. (2013). RNF38 encodes a nuclear ubiquitin protein ligase that modifies p53. Biochemical and Biophysical Research Communications, 440(4), 473–478. https://doi.org/10.1016/j.bbrc.2013.08.031
Shi, D., Pop, M. S., Kulikov, R., Love, I. M., Kung, A. L., & Grossman, S. R. (2009). CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53. Proceedings of the National Academy of Sciences of the United States of America, 106(38), 16275–16280. https://doi.org/10.1073/pnas.0904305106
Shieh, S. Y., Ikeda, M., Taya, Y., & Prives, C. (1997). DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell, 91(3), 325–334. https://doi.org/10.1016/s0092-8674(00)80416-x
Shloush, J., Vlassov, J. E., Engson, I., Duan, S., Saridakis, V., Dhe-Paganon, S., Raught, B., Sheng, Y., & Arrowsmith, C. H. (2011). Structural and functional comparison of the RING domains of two p53 E3 ligases, Mdm2 and Pirh2. Journal of Biological Chemistry, 286(6), 4796–4808. https://doi.org/10.1074/jbc.M110.157669
Singh, R. K., Iyappan, S., & Scheffner, M. (2007). Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2. Journal of Biological Chemistry, 282(15), 10901–10907. https://doi.org/10.1074/jbc.M610879200
Stevenson, L. F., Sparks, A., Allende-Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K. (2007). The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO Journal, 26(4), 976–986. https://doi.org/10.1038/sj.emboj.7601567
Stindt, M. H., Carter, S., Vigneron, A. M., Ryan, K. M., & Vousden, K. H. (2011). MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity. Cell Cycle, 10(18), 3176–3188. https://doi.org/10.4161/cc.10.18.17436
Sun, L., Shi, L., Li, W., Yu, W., Liang, J., Zhang, H., Yang, X., Wang, Y., Li, R., Yao, X., Yi, X., & Shang, Y. (2009). JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation. Proceedings of the National Academy of Sciences of the United States of America, 106(25), 10195–10200. https://doi.org/10.1073/pnas.0901864106
Sun, L., Shi, L., Wang, F., Huangyang, P., Si, W., Yang, J., Yao, Z., & Shang, Y. (2011). Substrate phosphorylation and feedback regulation in JFK-promoted p53 destabilization. Journal of Biological Chemistry, 286(6), 4226–4235. https://doi.org/10.1074/jbc.M110.195115
Sun, X. X., Challagundla, K. B., & Dai, M. S. (2012). Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. EMBO Journal, 31(3), 576–592. https://doi.org/10.1038/emboj.2011.434
Swatek, K. N., & Komander, D. (2016). Ubiquitin modifications. Cell Research, 26(4), 399–422. https://doi.org/10.1038/cr.2016.39
Takayama, K. I., Suzuki, T., Tanaka, T., Fujimura, T., Takahashi, S., Urano, T., Ikeda, K., & Inoue, S. (2018). TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer. Oncogene, 37(16), 2165–2180. https://doi.org/10.1038/s41388-017-0095-x
Tang, Y., Zhao, W., Chen, Y., Zhao, Y., & Gu, W. (2008). Acetylation is indispensable for p53 activation. Cell, 133(4), 612–626. https://doi.org/10.1016/j.cell.2008.03.025
Tatsumi, K., Sou, Y. S., Tada, N., Nakamura, E., Iemura, S., Natsume, T., Kang, S. H., Chung, C. H., Kasahara, M., Kominami, E., Yamamoto, M., Tanaka, K., & Komatsu, M. (2010). A novel type of E3 ligase for the Ufm1 conjugation system. Journal of Biological Chemistry, 285(8), 5417–5427. https://doi.org/10.1074/jbc.M109.036814
Tatsumi, K., Yamamoto-Mukai, H., Shimizu, R., Waguri, S., Sou, Y. S., Sakamoto, A., Taya, C., Shitara, H., Hara, T., Chung, C. H., Tanaka, K., Yamamoto, M., & Komatsu, M. (2011). The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. Nature Communications, 2, 181. https://doi.org/10.1038/ncomms1182
Taylor, J. L., D’Cunha, J., Tom, P., O’Brien, W. J., & Borden, E. C. (1996). Production of ISG-15, an interferon-inducible protein, in human corneal cells. Journal of Interferon and Cytokine Research, 16(11), 937–940. https://doi.org/10.1089/jir.1996.16.937
Ulrich, H. D. (2008). The fast-growing business of SUMO chains. Molecular Cell, 32(3), 301–305. https://doi.org/10.1016/j.molcel.2008.10.010
Unger, T., Juven-Gershon, T., Moallem, E., Berger, M., Vogt Sionov, R., Lozano, G., Oren, M., & Haupt, Y. (1999). Critical role for Ser20 of human p53 in the negative regulation of p53 by Mdm2. EMBO Journal, 18(7), 1805–1814. https://doi.org/10.1093/emboj/18.7.1805
Vertegaal, A. C. (2010). SUMO chains: Polymeric signals. Biochemical Society Transactions, 38(Pt 1), 46–49. https://doi.org/10.1042/BST0380046
Villarroya-Beltri, C., Baixauli, F., Mittelbrunn, M., Fernandez-Delgado, I., Torralba, D., Moreno-Gonzalo, O., Baldanta, S., Enrich, C., Guerra, S., & Sanchez-Madrid, F. (2016). (2016). ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nature Communications, 7, 13588. https://doi.org/10.1038/ncomms13588
Villarroya-Beltri, C., Guerra, S., & Sanchez-Madrid, F. (2017). ISGylation—A key to lock the cell gates for preventing the spread of threats. Journal of Cell Science, 130(18), 2961–2969. https://doi.org/10.1242/jcs.205468
Vousden, K. H., & Prives, C. (2009). Blinded by the light: the growing complexity of p53. Cell, 137(3), 413–431. https://doi.org/10.1016/j.cell.2009.04.037
Wada, H., Kito, K., Caskey, L. S., Yeh, E. T., & Kamitani, T. (1998). Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochemical and Biophysical Research Communications, 251(3), 688–692. https://doi.org/10.1006/bbrc.1998.9532
Walczak, C. P., Leto, D. E., Zhang, L., Riepe, C., Muller, R. Y., DaRosa, P. A., Ingolia, N. T., Elias, J. E., & Kopito, R. R. (2019). Ribosomal protein RPL26 is the principal target of UFMylation. Proc Natl Acad Sci U S A, 116(4), 1299–1308. https://doi.org/10.1073/pnas.1816202116
Wan, J., Block, S., Scribano, C. M., Thiry, R., Esbona, K., Audhya, A., & Weaver, B. A. (2019). Mad1 destabilizes p53 by preventing PML from sequestering MDM2. Nature Communications, 10(1), 1540. https://doi.org/10.1038/s41467-019-09471-9
Wang, L., Xu, Y., Rogers, H., Saidi, L., Noguchi, C. T., Li, H., Yewdell, J. W., Guydosh, N. R., & Ye, Y. (2020). UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis. Cell Research, 30(1), 5–20. https://doi.org/10.1038/s41422-019-0236-6
Wang, Y., Ding, Q., Xu, T., Li, C. Y., Zhou, D. D., & Zhang, L. (2017). HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma. Toxicology and Applied Pharmacology, 334, 180–191. https://doi.org/10.1016/j.taap.2017.09.011
Wang, Z., Gong, Y., Peng, B., Shi, R., Fan, D., Zhao, H., Zhu, M., Zhang, H., Lou, Z., Zhou, J., Zhu, W. G., Cong, Y. S., & Xu, X. (2019). MRE11 UFMylation promotes ATM activation. Nucleic Acids Research, 47(8), 4124–4135. https://doi.org/10.1093/nar/gkz110
Wang, Z., Zhu, W. G., & Xu, X. (2017). Ubiquitin-like modifications in the DNA damage response. Mutation Research, 803–805, 56–75. https://doi.org/10.1016/j.mrfmmm.2017.07.001
Watson, I. R., Li, B. K., Roche, O., Blanch, A., Ohh, M., & Irwin, M. S. (2010). Chemotherapy induces NEDP1-mediated destabilization of MDM2. Oncogene, 29(2), 297–304. https://doi.org/10.1038/onc.2009.314
Weger, S., Hammer, E., & Heilbronn, R. (2005). Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Letters, 579(22), 5007–5012. https://doi.org/10.1016/j.febslet.2005.07.088
Wei, T., Biskup, E., Gjerdrum, L. M., Niazi, O., Odum, N., & Gniadecki, R. (2016). Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma. Oncotarget, 7(30), 48391–48400. https://doi.org/10.18632/oncotarget.10268
Wei, W., Yang, P., Pang, J., Zhang, S., Wang, Y., Wang, M. H., Dong, Z., She, J. X., & Wang, C. Y. (2008). A stress-dependent SUMO4 sumoylation of its substrate proteins. Biochemical and Biophysical Research Communications, 375(3), 454–459. https://doi.org/10.1016/j.bbrc.2008.08.028
Wen, W., Peng, C., Kim, M. O., Ho Jeong, C., Zhu, F., Yao, K., Zykova, T., Ma, W., Carper, A., Langfald, A., Bode, A. M., & Dong, Z. (2014). Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. Oncogene, 33(4), 421–428. https://doi.org/10.1038/onc.2012.605
Wu, K., Yamoah, K., Dolios, G., Gan-Erdene, T., Tan, P., Chen, A., Lee, C. G., Wei, N., Wilkinson, K. D., Wang, R., & Pan, Z. Q. (2003). DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1. Journal of Biological Chemistry, 278(31), 28882–28891. https://doi.org/10.1074/jbc.M302888200
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993). The p53-mdm-2 autoregulatory feedback loop. Genes & Development, 7(7A), 1126–1132. https://doi.org/10.1101/gad.7.7a.1126
Xenaki, G., Ontikatze, T., Rajendran, R., Stratford, I. J., Dive, C., Krstic-Demonacos, M., & Demonacos, C. (2008). PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene, 27(44), 5785–5796. https://doi.org/10.1038/onc.2008.192
Xiang, S., Shao, X., Cao, J., Yang, B., He, Q., & Ying, M. (2020). FAT10: Function and relationship with cancer. Current Molecular Pharmacology, 13(3), 182–191. https://doi.org/10.2174/1874467212666191113130312
Xirodimas, D. P., Saville, M. K., Bourdon, J. C., Hay, R. T., & Lane, D. P. (2004). Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell, 118(1), 83–97. https://doi.org/10.1016/j.cell.2004.06.016
Xirodimas, D. P., Sundqvist, A., Nakamura, A., Shen, L., Botting, C., & Hay, R. T. (2008). Ribosomal proteins are targets for the NEDD8 pathway. EMBO Reports, 9(3), 280–286. https://doi.org/10.1038/embor.2008.10
Yang, J., Zhou, Y., Xie, S., Wang, J., Li, Z., Chen, L., Mao, M., Chen, C., Huang, A., Chen, Y., Zhang, X., Khan, N. U. H., Wang, L., & Zhou, J. (2021). Metformin induces ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. Journal of Experimental & Clinical Cancer Research, 40(1), 206. https://doi.org/10.1186/s13046-021-02012-7
Yates, K. E., Korbel, G. A., Shtutman, M., Roninson, I. B., & DiMaio, D. (2008). Repression of the SUMO-specific protease Senp1 induces p53-dependent premature senescence in normal human fibroblasts. Aging Cell, 7(5), 609–621. https://doi.org/10.1111/j.1474-9726.2008.00411.x
Yoo, H. M., Kang, S. H., Kim, J. Y., Lee, J. E., Seong, M. W., Lee, S. W., Ka, S. H., Sou, Y. S., Komatsu, M., Tanaka, K., Lee, S. T., Noh, D. Y., Baek, S. H., Jeon, Y. J., & Chung, C. H. (2014). Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Molecular Cell, 56(2), 261–274. https://doi.org/10.1016/j.molcel.2014.08.007
Yu, M., Shi, X., Ren, M., Liu, L., Qi, H., Zhang, C., Zou, J., Qiu, X., Zhu, W. G., Zhang, Y. E., Wang, W., & Luo, J. (2020). SIRT7 deacetylates STRAP to regulate p53 activity and stability. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms21114122
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010). USP10 regulates p53 localization and stability by deubiquitinating p53. Cell, 140(3), 384–396. https://doi.org/10.1016/j.cell.2009.12.032
Zhang, D. W., Jeang, K. T., & Lee, C. G. (2006). p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers. Oncogene, 25(16), 2318–2327. https://doi.org/10.1038/sj.onc.1209220
Zhang, M., Zhu, X., Zhang, Y., Cai, Y., Chen, J., Sivaprakasam, S., Gurav, A., Pi, W., Makala, L., Wu, J., Pace, B., Tuan-Lo, D., Ganapathy, V., Singh, N., & Li, H. (2015). RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death and Differentiation, 22(12), 1922–1934. https://doi.org/10.1038/cdd.2015.51
Zhang, S., & Sun, Y. (2020). Cullin RING Ligase 5 (CRL-5): Neddylation Activation and Biological Functions. Advances in Experimental Medicine and Biology, 1217, 261–283. https://doi.org/10.1007/978-981-15-1025-0_16
Zhang, X., Berger, F. G., Yang, J., & Lu, X. (2011). USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO Journal, 30(11), 2177–2189. https://doi.org/10.1038/emboj.2011.125
Zhang, Y., Cui, N., & Zheng, G. (2020). Ubiquitination of P53 by E3 ligase MKRN2 promotes melanoma cell proliferation. Oncology Letters, 19(3), 1975–1984. https://doi.org/10.3892/ol.2020.11261
Zhao, C., Beaudenon, S. L., Kelley, M. L., Waddell, M. B., Yuan, W., Schulman, B. A., Huibregtse, J. M., & Krug, R. M. (2004). The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein. Proc Natl Acad Sci U S A, 101(20), 7578–7582. https://doi.org/10.1073/pnas.0402528101
Zhou, Y., Ye, X., Zhang, C., Wang, J., Guan, Z., Yan, J., Xu, L., Wang, K., Guan, D., Liang, Q., Mao, J., Zhou, J., Zhang, Q., Wu, X., Wang, M., Cong, Y. S., & Liu, J. (2021). Ufl1 deficiency causes kidney atrophy associated with disruption of endoplasmic reticulum homeostasis. Journal of Genetics and Genomics, 48(5), 403–410. https://doi.org/10.1016/j.jgg.2021.04.006
Zhu, H., Bhatt, B., Sivaprakasam, S., Cai, Y., Liu, S., Kodeboyina, S. K., Patel, N., Savage, N. M., Sharma, A., Kaufman, R. J., Li, H., & Singh, N. (2019). Ufbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR. Nature Communications, 10(1), 1084. https://doi.org/10.1038/s41467-019-08908-5
Zou, Q., Jin, J., Hu, H., Li, H. S., Romano, S., Xiao, Y., Nakaya, M., Zhou, X., Cheng, X., Yang, P., Lozano, G., Zhu, C., Watowich, S. S., Ullrich, S. E., & Sun, S. C. (2014). USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nature Immunology, 15(6), 562–570. https://doi.org/10.1038/ni.2885
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We thank Dr. Yu-sheng Cong for critical reading of the manuscript. This work was supported by grants from the National Natural Science Foundation of China (31871416, 81871116).
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The original online version of this article was revised: Table 2 was missing from the original article and has now been added. Furthermore, the title of Table 1 has been corrected to “The effects of p53 ubiquitination”.
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Wang, Y., Zhang, C., Wang, J. et al. p53 regulation by ubiquitin and ubiquitin-like modifications. GENOME INSTAB. DIS. 3, 179–198 (2022). https://doi.org/10.1007/s42764-022-00067-0
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DOI: https://doi.org/10.1007/s42764-022-00067-0