Molecular recognition of p53 and MDM2 by USP7/HAUSP.

Sheng, Yi; Saridakis, Vivian; Sarkari, Feroz; Duan, Shili; Wu, Tianne; Arrowsmith, Cheryl H; Frappier, Lori

doi:10.1038/nsmb1067

Cited by 316Ubiquitin and proteasome pathwaysCancer-related Molecular PathwaysProtein Structure and Dynamics

Molecular recognition of p53 and MDM2 by USP7/HAUSP.

Sheng, Yi, Saridakis, Vivian, Sarkari, Feroz, Duan, Shili, Wu, Tianne, Arrowsmith, Cheryl H, Frappier, Lori·2006·Nature Structural & Molecular Biology

DOI 10.1038/nsmb1067

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Abstract

The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.

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USP7 TRAF-like domain residues D164 and W165 form essential contacts with P/A/ExxS motifs shared by all TRAF-like domain-binding substrates.
“The TRAF-like domain assumes an eight stranded antiparallel β- sandwich fold, with residues D164 and W165 forming essential contacts with P/A/ExxS motifs shared by all TRAF-like domain-binding substrates.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Sheng et al., 2006
Mdm2 binds the USP7 TRAF-like domain with higher affinity than p53 because Mdm2 makes more extensive contacts.
“An obstacle to this switch is that while USP7 binds both Mdm2 and p53 via its TRAF-like domain, Mdm2 makes more extensive contacts and thus binds the TRAF-like domain with a higher affinity (Hu et al., 2006; Sheng et al., 2006).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Sheng et al., 2006
USP7 has a central role in stabilizing p53 protein levels in response to genomic stress.
“As discussed in previous sections, USP7 has a central role in stabilizing p53 protein levels in response to genomic stress (Sheng et al., 2006).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Sheng et al., 2006
Mdm2 seems to be a better binding partner of HAUSP than p53.
“Mdm2 seems to be a better binding partner of HAUSP than p53”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Sheng et al., 2006

[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Improved methods for building protein models in electron density maps and the location of errors in these models
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
A marker for Stevens–Johnson syndrome
Chung, W., Chung, W., Hong, H., Hsih, M., Yang, L., Ho, H., Wu, J., & Chen, Y.-T. (2004) · Nature · doi:10.1038/428486a · Cited by 1,748 · see citing works
Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization
Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J., & Gu, W. J. (2002) · Nature · doi:10.1038/nature737 · Cited by 1,027 · see citing works
A dynamic role of HAUSP in the p53-Mdm2 pathway
Li, M., Brooks, C. L., Kon, N., & Gu, W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00157-1 · Cited by 679 · see citing works
Distinct molecular mechanism for initiating TRAF6 signalling
Ye, H., Arron, J. R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N. K., Segal, D., Dzivenu, O. K., Vologodskaia, M., Yim, M., et al. (2002) · Nature · doi:10.1038/nature00888 · Cited by 665 · see citing works
Crystal Structure of a UBP-Family Deubiquitinating Enzyme in Isolation and in Complex with Ubiquitin Aldehyde
Hu, M., Li, P., Li, M., Li, W., Yao, T., Wu, J.-W., Gu, W. J., Cohen, R. E., & Shi, Y. (2002) · Cell · doi:10.1016/s0092-8674(02)01199-6 · Cited by 648 · see citing works
A novel ubiquitin‐specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein
Everett, R. D., Meredith, M., Orr, A., Cross, A., Kathoria, M., & Parkinson, J. (1997) · The EMBO Journal · doi:10.1093/emboj/16.7.1519 · Cited by 491 · see citing works
Multiple C-Terminal Lysine Residues Target p53 for Ubiquitin-Proteasome-Mediated Degradation
Rodríguez, M. S., Desterro, J. M. P., Laı́n, S., Lane, D. P., & Hay, R. T. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.22.8458-8467.2000 · Cited by 386 · see citing works
Disruption of HAUSP gene stabilizes p53.
Cummins, J. M., Rago, C., Kohli, M., Kinzler, K. W., Lengauer, C., & Vogelstein, B. (2004) · Nature · doi:10.1038/nature02501 · Cited by 379 · see citing works
Structure of the p53 Binding Domain of HAUSP/USP7 Bound to Epstein-Barr Nuclear Antigen 1
Saridakis, V., Sheng, Y., Sarkari, F., Holowaty, M. N., Shire, K., Nguyen, T., Zhang, R. G., Liao, J. C. C., Lee, W., Edwards, A. M., et al. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.02.029 · Cited by 362 · see citing works
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Ye, H., Park, Y. C., Kreishman, M., Kieff, E. D., & Wu, H. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80334-2 · Cited by 292 · see citing works
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Meulmeester, E., Maurice, M. M., Boutell, C., Teunisse, A. F. A. S., Ovaa, H., Abraham, T. E., Dirks, R. W., & Jochemsen, A. G. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.024 · Cited by 260 · see citing works
Protein Profiling with Epstein-Barr Nuclear Antigen-1 Reveals an Interaction with the Herpesvirus-associated Ubiquitin-specific Protease HAUSP/USP7
Holowaty, M. N., Zeghouf, M., Wu, H., Tellam, J., Athanasopoulos, V., Greenblatt, J., & Frappier, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303977200 · Cited by 228 · see citing works
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Cummins, J. M., & Vogelstein, B. (2004) · Cell Cycle · doi:10.4161/cc.3.6.924 · Cited by 188 · see citing works
Protein Interaction Domains of the Ubiquitin-specific Protease, USP7/HAUSP
Holowaty, M. N., Sheng, Y., Nguyen, T., Arrowsmith, C. H., & Frappier, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307200200 · Cited by 182 · see citing works
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Meredith, M., Orr, A., & Everett, R. D. (1994) · Virology · doi:10.1006/viro.1994.1209 · Cited by 85 · see citing works

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Reyes-Turcu, F. E., Ventii, K. H., & Wilkinson, K. D. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.082307.091526 · Cited by 1,396 · see citing works
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Joerger, A. C., & Fersht, A. R. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.060806.091238 · Cited by 699 · see citing works
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Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637 · see citing works
“In fact, Mdm2 seems to be a better binding partner of HAUSP than p53 (Hu et al., 2006; Sheng et al., 2006).”
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
The role of ubiquitination and deubiquitination in cancer metabolism
Sun, T., Liu, Z., & Yang, Q. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01262-x · Cited by 518 · see citing works
Short Linear Motifs: Ubiquitous and Functionally Diverse Protein Interaction Modules Directing Cell Regulation
Roey, K. V., Uyar, B., Weatheritt, R. J., Dinkel, H., Seiler, M., Budd, A., Gibson, T. J., & Davey, N. E. (2014) · Chemical Reviews · doi:10.1021/cr400585q · Cited by 496 · see citing works
How viruses hijack cell regulation
Davey, N. E., Travé, G., & Gibson, T. J. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.10.002 · Cited by 383 · see citing works
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Snyder, N. A., & Silva, G. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101077 · Cited by 352 · see citing works
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Stevenson, L. F., Sparks, A., Allende‐Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601567 · Cited by 280 · see citing works
MDM2 and MDM4: p53 regulators as targets in anticancer therapy
Toledo, F., & Wahl, G. M. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.03.022 · Cited by 261 · see citing works
Mechanism of USP7/HAUSP Activation by Its C-Terminal Ubiquitin-like Domain and Allosteric Regulation by GMP-Synthetase
Faesen, A. C., Dirac, A. M. G., Shanmugham, A., Ovaa, H., Anastassis Perrakis, A., & Sixma, T. K. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.034 · Cited by 251 · see citing works
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Wang, Y., Yang, L., Zhang, X., Cui, W., Liu, Y., Sun, Q., He, Q., Zhao, S., Zhang, G., Wang, Y., et al. (2019) · EMBO Reports · doi:10.15252/embr.201847563 · Cited by 215 · see citing works
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Renatus, M., Gil-Parrado, S., D'Arcy, A., Eidhoff, U., Gerhartz, B., Hassiepen, U., Pierrat, B., Riedl, R., Vinzenz, D., Worpenberg, S., et al. (2006) · Structure · doi:10.1016/j.str.2006.06.012 · Cited by 212 · see citing works
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Hao, Y.-H., Fountain, M. D., Fon Tacer, K., Xia, F., Bi, W., Kang, S.-H. L., Patel, A., Rosenfeld, J. A., Le Caignec, C., Isidor, B., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.033 · Cited by 206 · see citing works
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Pal, A., Young, M. A., & Donato, N. J. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1211 · Cited by 198 · see citing works
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Uversky, V. N. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17111874 · Cited by 193 · see citing works
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Pan, J., Deng, Q., Jiang, C., Wang, X., Niu, T., Li, H., Chen, T., Jin, J., Pan, W., Cai, X., et al. (2014) · Oncogene · doi:10.1038/onc.2014.327 · Cited by 169 · see citing works
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Novellasdemunt, L., Foglizzo, V., Gómez-Cuadrado, L., Antas, P., Kucharska, A., Encheva, V., Snijders, A. P., & Li, V. S. W. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.072 · Cited by 163 · see citing works
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Qi, S., Cheng, G., Cheng, X., Xu, Z., Xu, B., Zhang, W., & Qin, J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00233 · Cited by 162 · see citing works
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Mittler, G., Butter, F., & Mann, M. (2008) · Genome Research · doi:10.1101/gr.081711.108 · Cited by 162 · see citing works
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Huang, Z., Wu, Q., Guryanova, O. A., Cheng, L., Shou, W., Rich, J. N., & Bao, S. (2011) · Nature Cell Biology · doi:10.1038/ncb2153 · Cited by 160 · see citing works
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Meitinger, F., Ohta, M., Lee, K.-Y., Watanabe, S., Davis, R. L., Anzola, J. V., Kabeche, R., Jenkins, D. A., Shiau, A. K., Desai, A. B., et al. (2020) · Nature · doi:10.1038/s41586-020-2710-1 · Cited by 155 · see citing works
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Daubeuf, S., Singh, D., Tan, Y., Liu, H., Federoff, H. J., Bowers, W. J., & Tolba, K. A. (2008) · Blood · doi:10.1182/blood-2008-07-168203 · Cited by 146 · see citing works
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Brooks, C. L., Li, M., Hu, M., Shi, Y., & Gu, W. (2007) · Oncogene · doi:10.1038/sj.onc.1210531 · Cited by 144 · see citing works
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Buac, D., Shen, M., Schmitt, S. M., Kona, F. R., Deshmukh, R. R., Zhang, Z., Neslund-Dudas, C. M., Mitra, B., & Dou, Q. P. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319220012 · Cited by 138 · see citing works
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Wood, V. H. J., O’Neil, J. D., Wei, W., Stewart, S. E., Dawson, W. O., & Young, L. S. (2007) · Oncogene · doi:10.1038/sj.onc.1210496 · Cited by 136 · see citing works
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Ji, L., Lu, B., Zamponi, R., Charlat, O., Aversa, R. J., Yang, Z., Sigoillot, F. D., Zhu, X., Hu, T., Reece-Hoyes, J. S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12143-3 · Cited by 129 · see citing works
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Sahtoe, D. D., & Sixma, T. K. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.05.002 · Cited by 127 · see citing works
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Frappier, L. (2012) · Viruses · doi:10.3390/v4091537 · Cited by 127 · see citing works
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Zou, T., & Lin, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115754 · Cited by 120 · see citing works
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Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
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BackgroundInfluential
p53 stability is regulated by diverse deubiquitinating enzymes
Kwon, S., Saindane, M., & Baek, K. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.08.001 · Cited by 110 · see citing works
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Rougé, L., Bainbridge, T. W., Kwok, M., Tong, R., Di Lello, P., Wertz, I. E., Maurer, T., Ernst, J. A., & Murray, J. (2016) · Structure · doi:10.1016/j.str.2016.05.020 · Cited by 108 · see citing works
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Tavana, O., & Gu, W. J. (2016) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjw049 · Cited by 108 · see citing works
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He, M., Zhou, Z., Shah, A. A., Zou, H., Tao, J., Chen, Q., & Wan, Y. (2016) · Cell & Bioscience · doi:10.1186/s13578-016-0127-1 · Cited by 106 · see citing works
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Heideker, J., & Wertz, I. E. (2014) · Biochemical Journal · doi:10.1042/bj20140496 · Cited by 100 · see citing works
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Frappier, L. (2012) · Scientifica · doi:10.6064/2012/438204 · Cited by 97 · see citing works
Self-citation
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Nathan, J. A., Sengupta, S., Wood, S. A., Admon, A., Markson, G., Sanderson, C. M., & Lehner, P. J. (2008) · Traffic · doi:10.1111/j.1600-0854.2008.00747.x · Cited by 97 · see citing works
Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.
Fernández‐Montalván, A., Bouwmeester, T., Joberty, G., Mader, R., Mahnke, M., Pierrat, B., Schlaeppi, J., Worpenberg, S., & Gerhartz, B. (2007) · The FEBS Journal · doi:10.1111/j.1742-4658.2007.05952.x · Cited by 96 · see citing works
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Kim, R. Q., & Sixma, T. K. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.05.028 · Cited by 96 · see citing works
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Pereg, Y., Lam, S., Teunisse, A., Biton, S., Meulmeester, E., Mittelman, L., Buscemi, G., Okamoto, K., Taya, Y., Shiloh, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00562-06 · Cited by 93 · see citing works
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Wilson, J. B., Manet, É., Gruffat, H., Busson, P., Blondel, M., & Fåhræus, R. (2018) · Cancers · doi:10.3390/cancers10040109 · Cited by 93 · see citing works
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Nininahazwe, L., Liu, B., He, C., Zhang, H., & Chen, Z. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.10.028 · Cited by 92 · see citing works
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Self-citation
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Zapata, J. M., Martínez-García, V., & Lefebvre, S. (2007) · Springer eBooks · doi:10.1007/978-0-387-70630-6_1 · Cited by 88 · see citing works
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Ouyang, L., Yan, B., Liu, Y., Mao, C., Wang, M., Liu, N., Wang, Z., Liu, S., Shi, Y., Chen, L., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0181-3 · Cited by 87 · see citing works
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Dar, A., Shibata, E., & Dutta, A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00358-13 · Cited by 83 · see citing works
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Zarzycka, B. A., Seijkens, T. T. P., Nabuurs, S. B., Ritschel, T., Grommes, J., Soehnlein, O., Schrijver, R., van Tiel, C. M., Hackeng, T. M., Weber, C., et al. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/ci500631e · Cited by 82 · see citing works
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Li, Y., & Reverter, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22030986 · Cited by 82 · see citing works
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Lee, H.-R., Choi, W., Lee, S., Hwang, J., Hwang, E., Guchhait, K., Haas, J., Tóth, Z., Jeon, Y. H., Oh, T.-K., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2142 · Cited by 81 · see citing works
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Cao, J. Y., Mansouri, S., & Frappier, L. (2011) · Journal of Virology · doi:10.1128/jvi.05648-11 · Cited by 79 · see citing works
Self-citation
EBNA1
Frappier, L. (2015) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-22834-1_1 · Cited by 78 · see citing works
Self-citation
USP7 is essential for maintaining Rad18 stability and DNA damage tolerance.
Zlatanou, A., Sabbioneda, S., Miller, E. S., Greenwalt, A., Aggathanggelou, A., Maurice, M. M., Lehmann, A. R., Stankovic, T., Reverdy, C., Colland, F., et al. (2016) · Oncogene · doi:10.1038/onc.2015.149 · Cited by 77 · see citing works
USP17 Regulates Ras Activation and Cell Proliferation by Blocking RCE1 Activity
Burrows, J. F., Kelvin, A. A., McFarlane, C., Burden, R. E., McGrattan, M. J., de la Vega, M., Govender, U., Quinn, D. J., Dib, K., Gadina, M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807216200 · Cited by 76 · see citing works
Linear motifs confer functional diversity onto splice variants
Weatheritt, R. J., Davey, N. E., & Gibson, T. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks442 · Cited by 76 · see citing works
Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7
Pfoh, R., Lacdao, I. K., Georges, A. A., Capar, A., Zheng, H. X., Frappier, L., & Saridakis, V. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004950 · Cited by 72 · see citing works
Self-citation
A role for USP7 in DNA replication.
Jagannathan, M., Nguyen, T., Gallo, D., Luthra, N., Brown, G. W., Saridakis, V., & Frappier, L. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00639-13 · Cited by 71 · see citing works
Self-citation
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Ruano, Y., Mollejo, M., Camacho, F. I., de Lope, Á. R., Fiaño, C., Ribalta, T., Martínez, P., Hernández-Moneo, J.-L., & Meléndez, B. (2008) · Cancer · doi:10.1002/cncr.23338 · Cited by 71 · see citing works
Regulation of the DNA damage response by ubiquitin conjugation
Brinkmann, K., Schell, M. J., Hoppe, T., & Kashkar, H. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00098 · Cited by 70 · see citing works
Deubiquitination in virus infection
Lindner, H. A. (2007) · Virology · doi:10.1016/j.virol.2006.12.035 · Cited by 69 · see citing works
C-terminal region of USP7/HAUSP is critical for deubiquitination activity and contains a second mdm2/p53 binding site
Ma, J., Martin, J. D., Xue, Y., Lor, L. A., Kennedy-Wilson, K. M., Sinnamon, R. H., Ho, T. F., Zhang, G., Schwartz, B. K., Tummino, P. J., et al. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.08.020 · Cited by 67 · see citing works
Genome-wide interrogation of gene functions through base editor screens empowered by barcoded sgRNAs
Xu, P., Liu, Z., Liu, Y., Ma, H., Xu, Y., Bao, Y., Zhu, S., Cao, Z., Wu, Z., Zhou, Z. L., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00944-1 · Cited by 66 · see citing works
The role of UBL domains in ubiquitin-specific proteases
Faesen, A. C., Luna‐Vargas, M. P. A., & Sixma, T. K. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120004 · Cited by 66 · see citing works
The Ubiquitin-Specific Protease USP7 Modulates the Replication of Kaposi's Sarcoma-Associated Herpesvirus Latent Episomal DNA
Jäger, W., Santag, S., Weidner-Glunde, M., Gellermann, E., Kati, S., Pietrek, M., Viejo‐Borbolla, A., & Schulz, T. F. (2012) · Journal of Virology · doi:10.1128/jvi.06840-11 · Cited by 65 · see citing works
A role of HAUSP in tumor suppression in a human colon carcinoma xenograft model.
Becker, K., Marchenko, N., Palacios, G., & Moll, U. M. (2008) · Cell Cycle · doi:10.4161/cc.7.9.5756 · Cited by 63 · see citing works
USP2a Protein Deubiquitinates and Stabilizes the Circadian Protein CRY1 in Response to Inflammatory Signals
Tong, X., Buelow, K. L., Guha, A., Rausch, R., & Yin, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340786 · Cited by 63 · see citing works
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Georges, A. A., Marcon, E., Greenblatt, J. F., & Frappier, L. (2018) · Scientific Reports · doi:10.1038/s41598-018-34197-x · Cited by 63 · see citing works
Self-citation
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Rodríguez, J., Herrero, A., Li, S., Rauch, N., Quintanilla, A., Wynne, K. J., Krstić, A., Acosta, J. C., Taylor, C. T., Schlisio, S., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.108 · Cited by 62 · see citing works
The herpesvirus associated ubiquitin specific protease, USP7, is a negative regulator of PML proteins and PML nuclear bodies.
Sarkari, F., Wang, X., Nguyen, T., & Frappier, L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016598 · Cited by 59 · see citing works
Self-citation
USP7 Cooperates with SCML2 To Regulate the Activity of PRC1
Lecona, E., Narendra, V. K., & Reinberg, D. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.01197-14 · Cited by 59 · see citing works
Gene expression control by protein deubiquitinases
Frappier, L., & Verrijzer, C. P. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.02.005 · Cited by 58 · see citing works
Self-citation
The USP7 protein interaction network and its roles in tumorigenesis
Al-Eidan, A., Wang, Y., Skipp, P., & Ewing, R. M. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2020.10.004 · Cited by 57 · see citing works
Latent membrane protein 1 of Epstein-Barr virus regulates p53 phosphorylation through MAP kinases
Li, L., Guo, L., Tao, Y., Zhou, S., Wang, Z., Luo, W., Hu, D., Li, Z., Xiao, L., Tang, M., et al. (2007) · Cancer Letters · doi:10.1016/j.canlet.2007.04.014 · Cited by 57 · see citing works
Cracking the Ubiquitin Code: The Ubiquitin Toolbox
Mulder, M. P. C., Witting, K. F., & Ovaa, H. (2019) · Current Issues in Molecular Biology · doi:10.21775/cimb.037.001 · Cited by 57 · see citing works
Structure of USP7 catalytic domain and three Ubl-domains reveals a connector α-helix with regulatory role
Kim, R. Q., van Dijk, W. J., & Sixma, T. K. (2016) · Journal of Structural Biology · doi:10.1016/j.jsb.2016.05.005 · Cited by 56 · see citing works
USP7‐TRIM27 axis negatively modulates antiviral type I IFN signaling
Cai, J., Chen, H., Peng, S., Meng, J., Wang, Y., Zhou, Y. J., Qian, X., Sun, X., Pang, X., Zhang, Y., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201700473rr · Cited by 55 · see citing works
Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7.
Sarkari, F., La Delfa, A., Arrowsmith, C. H., Frappier, L., Sheng, Y., & Saridakis, V. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.08.017 · Cited by 54 · see citing works
Self-citation
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Mungamuri, S. K., Qiao, R. F., Yao, S., Manfredi, J. J., Gu, W., & Aaronson, S. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.049 · Cited by 54 · see citing works
The ISG15-specific protease USP18 regulates stability of PTEN
Mustachio, L. M., Kawakami, M., Lu, Y., Rodriguez‐Canales, J., Mino, B., Behrens, C., Wistuba, I. I., Bota‐Rabassedas, N., Yu, J. Q., Lee, J. J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.13914 · Cited by 54 · see citing works
USP7 deubiquitinase controls HIV-1 production by stabilizing Tat protein
Ali, A., Raja, R., Farooqui, S. R., Ahmad, S., & Banerjea, A. C. (2017) · Biochemical Journal · doi:10.1042/bcj20160304 · Cited by 54 · see citing works
Nuclear deubiquitination in the spotlight: the multifaceted nature of USP7 biology in disease
Rawat, R., Starczynowski, D. T., & Ntziachristos, P. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.02.008 · Cited by 53 · see citing works
Insights into the ubiquitin-proteasome system of human embryonic stem cells
Sáez, I., Koyuncu, S., Gutiérrez-García, R., Dieterich, C., & Vı́lchez, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-22384-9 · Cited by 52 · see citing works
Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy
Lai, K. P., Chen, J., & Tse, W. K. F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072548 · Cited by 51 · see citing works
The deubiquitinases UBP12 and UBP13 integrate with the E3 ubiquitin ligase XBAT35.2 to modulate VPS23A stability in ABA signaling
Liu, G., Liang, J., Lou, L., Tian, M., Zhang, X.-Y., Liu, L., Zhao, Q., Xia, R., Wu, Y., Xie, Q., et al. (2022) · Science Advances · doi:10.1126/sciadv.abl5765 · Cited by 49 · see citing works
Evolutionarily conserved regulators of tau identify targets for new therapies
Kim, J., de Haro, M., Al‐Ramahi, I., Garaicoechea, L. L., Jeong, H.-H., Sonn, J. Y., Tadros, B., Liu, Z., Botas, J., & Zoghbi, H. Y. (2023) · Neuron · doi:10.1016/j.neuron.2022.12.012 · Cited by 49 · see citing works
Structure and Catalytic Regulatory Function of Ubiquitin Specific Protease 11 N-Terminal and Ubiquitin-like Domains
Harper, S. J., Gratton, H. E., Cornaciu, I., Oberer, M., Scott, D. J., Emsley, J., & Dreveny, I. (2014) · Biochemistry · doi:10.1021/bi500116x · Cited by 49 · see citing works

Structural Basis of Competitive Recognition of p53 and MDM2 by HAUSP/USP7: Implications for the Regulation of the p53–MDM2 Pathway
Hu, M., Gu, L., Li, M., Jeffrey, P. D., Gu, W., & Shi, Y. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040027 · Cited by 251 · see citing works
Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7.
Sarkari, F., La Delfa, A., Arrowsmith, C. H., Frappier, L., Sheng, Y., & Saridakis, V. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.08.017 · Cited by 54 · see citing works
Self-citation
Structural Basis of Competitive Recognition of p53 and MDM2 by HAUSP/USP7: Implications for the Regulation of the p53–MDM2 Pathway-0
Min Hu, L. G. (2011) · Figshare · doi:10.6084/m9.figshare.52567
Protein Interaction Domains of the Ubiquitin-specific Protease, USP7/HAUSP
Holowaty, M. N., Sheng, Y., Nguyen, T., Arrowsmith, C. H., & Frappier, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307200200 · Cited by 182 · see citing works
Self-citation
Molecular mechanism for the substrate recognition of USP7
Cheng, J., Li, Z., Gong, R., Fang, J., Yang, Y., Sun, C., Yang, H., & Xu, Y. (2015) · Protein & Cell · doi:10.1007/s13238-015-0192-y · Cited by 27 · see citing works

Authors: Sheng, Y., Saridakis, V., Sarkari, F., Duan, S., Wu, T., Arrowsmith, C. H., & Frappier, L.
Affiliations: University of Toronto (CA)
Corresponding author: Frappier, Lori
ORCID: Sheng, Yi
Duan, Shili
Arrowsmith, Cheryl H
Frappier, Lori
Venue: Nature Structural & Molecular Biology
Publisher: Springer Science and Business Media LLC
Published: 2006-02-12
Volume: 13
Issue: 3
Pages: 285-291
ISSN: 1545-9985 (ISSN-L)
1545-9993
DOI: 10.1038/nsmb1067
OpenAlex: W2032610349
Cited by: 315
References: 19
Citations by year: 2026: 19 · 2025: 24 · 2024: 16 · 2023: 20 · 2022: 21 · 2021: 19 · 2020: 22 · 2019: 25 · 2018: 14 · 2017: 11 · 2016: 16 · 2015: 22 · 2014: 10 · 2013: 13 · 2012: 10
FWCI: 4.62
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Structural & Molecular Biology (publishedVersion)
PubMed (publishedVersion)
Funders: Terry Fox Foundation
Natural Sciences and Engineering Research Council of Canada
National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: USP7, p53, MDM2, ubiquitin-specific protease, protein-protein interaction, substrate recognition, peptide binding, co-crystal structure, p53 stabilization, serine residues
MeSH terms: Ubiquitin-Specific Peptidase 7, Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Endopeptidases, Peptides, Protein Binding, Protein Conformation, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Crystallography, X-Ray, Amino Acid Motifs, Protein Interaction Mapping, Ubiquitin Thiolesterase, Proto-Oncogene Proteins c-mdm2

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Molecular recognition of p53 and MDM2 by USP7/HAUSP.

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