An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1.
Open accessAbstract
The protein stability and chromatin functions of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) are regulated in a cell-cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of the UHRF1 PBR overlaps with the region engaging in an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-"occluded" state to a state open for multivalent histone binding. Consistently, introduction of a USP7-interaction-defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The UBL 1-2 domains contain the second major substrate recognition site for USP7 substrates.
“Outside of the TRAF-like domain, the UBL 1–2 domains contain the second major substrate recognition site for USP7 substrates.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zhang et al., 2015
The UBL 1-2 acidic interface interacts with a highly basic motif (R/KxKxxxK) within USP7 substrates including UHRF1, DNMT1 and RNF169.
“This acidic interface interacts with a highly basic motif (R/KxKxxxK) within USP7 substrates that include UHRF1 (Zhang et al., 2015), DNMT1 (Cheng et al., 2015) and RNF169 (An et al., 2017; Figure 1 and Table 1).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zhang et al., 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,994 · see citing works
<i>PHENIX</i> : building new software for automated crystallographic structure determination
Adams, P. D., Grosse-Kunstleve, R. W., Hung, L.-W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., & Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016657 · Cited by 4,361 · see citing works
UHRF1 Plays a Role in Maintaining DNA Methylation in Mammalian Cells
Bostick, M. L., Kim, J. K., Estève, P., Clark, A. T., Pradhan, S., & Jacobsen, S. E. (2007) · Science · doi:10.1126/science.1147939 · Cited by 1,459 · see citing works
The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA
Sharif, J., Muto, M., Takebayashi, S., Suetake, I., Iwamatsu, A., Endo, T. A., Shinga, J., Mizutani-Koseki, Y., Toyoda, T., Okamura, K., et al. (2007) · Nature · doi:10.1038/nature06397 · Cited by 1,307 · see citing works
Perceiving the epigenetic landscape through histone readers
Musselman, C. A., Lalonde, M., Côté, J., & Kutateladze, T. G. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2436 · Cited by 840 · see citing works
Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism
Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y., & Shirakawa, M. (2008) · Nature · doi:10.1038/nature07249 · Cited by 517 · see citing works
Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1
Avvakumov, G. V., Walker, J. R., Xue, S., Li, Y., Duan, S., Bronner, C., Arrowsmith, C. H., & Dhe‐Paganon, S. (2008) · Nature · doi:10.1038/nature07273 · Cited by 490 · see citing works
DNA methylation and methyl-CpG binding proteins: developmental requirements and function
Bogdanović, O., & Veenstra, G. J. C. (2009) · Chromosoma · doi:10.1007/s00412-009-0221-9 · Cited by 474 · see citing works
Rigbolt, K. T. G., Prokhorova, T. A., Akimov, V., Henningsen, J., Johansen, P. T., Kratchmarova, I., Kassem, M., Mann, M., Olsen, J. V., & Blagoev, B. (2011) · Science Signaling · doi:10.1126/scisignal.2001570 · Cited by 451 · see citing works
The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix
Hashimoto, H., Horton, J. R., Zhang, X., Bostick, M. L., Jacobsen, S. E., & Cheng, X. (2008) · Nature · doi:10.1038/nature07280 · Cited by 448 · see citing works
Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication
Nishiyama, A., Yamaguchi, L., Sharif, J., Johmura, Y., Kawamura, T., Nakanishi, K., Shimamura, S., Arita, K., Kodama, T., Ishikawa, F., et al. (2013) · Nature · doi:10.1038/nature12488 · Cited by 410 · see citing works
Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation
Rothbart, S. B., Krajewski, K., Nady, N., Tempel, W., Xue, S., Badeaux, A. I., Baršytė-Lovejoy, D., Martínez-Márquez, J. Y., Bedford, M. T., Fuchs, S. M., et al. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2391 · Cited by 381 · see citing works
Self-citationDu, Z., Song, J. K., Wang, Y., Zhao, Y., Guda, K., Yang, S., Kao, H., Xu, Y., Willis, J. E., Markowitz, S. D., et al. (2010) · Science Signaling · doi:10.1126/scisignal.2001462 · Cited by 337 · see citing works
Self-citationDNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination
Qin, W., Wolf, P., Liu, N., Link, S., Smets, M., Mastra, F. L., Forné, I., Pichler, G., Hörl, D., Fellinger, K., et al. (2015) · Cell Research · doi:10.1038/cr.2015.72 · Cited by 259 · see citing works
Karagianni, P., Amazit, L., Qin, J., & Wong, J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01598-07 · Cited by 249 · see citing works
Recognition of Multivalent Histone States Associated with Heterochromatin by UHRF1 Protein
Nady, N., Lemak, A. S., Walker, J. R., Avvakumov, G. V., Kareta, M. S., Achour, M., Xue, S., Duan, S., Allali‐Hassani, A., Zuo, X., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.234104 · Cited by 235 · see citing works
Self-citationArita, K., Isogai, S., Oda, T., Unoki, M., Sugita, K., Sekiyama, N., Kuwata, K., Hamamoto, R., Tochio, H., Sato, M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203701109 · Cited by 229 · see citing works
Tip60 acetylates six lysines of a specific class in core histones in vitro
Kimura, A., & Horikoshi, M. (1998) · Genes to Cells · doi:10.1046/j.1365-2443.1998.00229.x · Cited by 215 · see citing works
Rajakumara, E., Wang, Z., Ma, H., Hu, L., Chen, H., Lin, Y., Guo, R., Wu, F., Li, H., Lan, F., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.07.006 · Cited by 209 · see citing works
Rothbart, S. B., Dickson, B. M., Ong, M. S., Krajewski, K., Houliston, S., Kireev, D., Arrowsmith, C. H., & Strahl, B. D. (2013) · Genes & Development · doi:10.1101/gad.220467.113 · Cited by 201 · see citing works
Self-citationFelle, M., Joppien, S., Németh, A., Diermeier, S. D., Thalhammer, V., Dobner, T., Kremmer, E., Kappler, R., & Längst, G. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr528 · Cited by 198 · see citing works
Cheng, J., Yang, Y., Fang, J., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.415398 · Cited by 137 · see citing works
Clarke, J. H., Letcher, A. J., D’Santos, C. S., et al. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3570905 · Cited by 135 · see citing works
Gelato, K. A., Tauber, M., Ong, M. S., Winter, S., Hiragami-Hamada, K., Sindlinger, J., Lemak, A. S., Bultsma, Y., Houliston, S., Schwarzer, D., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.004 · Cited by 127 · see citing works
Ma, H., Chen, H., Guo, X., Wang, Z., Sowa, M. E., Zheng, L., Hu, S., Zeng, P.-Y., Guo, R., Diao, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116349109 · Cited by 117 · see citing works
Xie, S., Jakoncic, J., & Qian, C. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.11.012 · Cited by 109 · see citing works
Clarke, J. H., Letcher, A. J., D’Santos, C. S., et al. (2001) · Biochemical Journal · doi:10.1042/bj3570905 · Cited by 108 · see citing works
Hu, L., Li, Z., Wang, P., et al. (2011) · Cell Research · doi:10.1038/cr.2011.124 · Cited by 96 · see citing works
Np95 Is Implicated in Pericentromeric Heterochromatin Replication and in Major Satellite Silencing
Papait, R., Pistore, C., Negri, D., Pecoraro, D., Cantarini, L., & Bonapace, I. M. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-09-0874 · Cited by 86 · see citing works
Peptide Microarrays to Interrogate the “Histone Code”
Rothbart, S. B., Krajewski, K., Strahl, B. D., & Fuchs, S. M. (2012) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-391940-3.00006-8 · Cited by 70 · see citing works
Self-citationUHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis
Chu, J., Loughlin, E. A., Gaur, N. A., SenBanerjee, S., Jacob, V., Monson, C., Kent, B., Oranu, A. C., Ding, Y., Ukomadu, C., et al. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-06-0487 · Cited by 50 · see citing works
The PHD Finger of Human UHRF1 Reveals a New Subgroup of Unmethylated Histone H3 Tail Readers
Lallous, N., Legrand, P., McEwen, A. G., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027599 · Cited by 48 · see citing works
Miura, M., Watanabe, H., Sasaki, T., et al. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5115 · Cited by 47 · see citing works
MBD4 Interacts With and Recruits USP7 to Heterochromatic Foci
Meng, H., Harrison, D. J., & Meehan, R. R. (2014) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25001 · Cited by 23 · see citing works
Depletion of Uhrf1 inhibits chromosomal DNA replication in Xenopus egg extracts
Taylor, E. M., Bonsu, N. M., Price, R. J., & Lindsay, H. D. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt549 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ferry, L., Fournier, A., Tsusaka, T., Adelmant, G., Shimazu, T., Matano, S., Kirsh, O., Amouroux, R., Dohmae, N., Suzuki, T., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.07.012 · Cited by 203 · see citing works
USP7: Structure, substrate specificity, and inhibition
Pozhidaeva, A., & Bezsonova, I. (2019) · DNA Repair · doi:10.1016/j.dnarep.2019.02.005 · Cited by 178 · see citing works
USP7 Is a Master Regulator of Genome Stability
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
“This acidic interface interacts with a highly basic motif (R/KxKxxxK) within USP7 substrates that include UHRF1 (Zhang et al., 2015), DNMT1 (Cheng et al., 2015) and RNF169 (An et al., 2017; Figure 1 and Table 1).”
BackgroundInfluentialMolecular understanding of USP7 substrate recognition and c-terminal activation.
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
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
Self-citationUSP7 deubiquitinates and stabilizes SIRT1.
Song, N., Cao, C., Tian, S., Long, M., & Liu, L. (2020) · The Anatomical Record · doi:10.1002/ar.24252 · Cited by 19 · see citing works
- Authors
- Zhang, Z.-M., Rothbart, S. B., Allison, D. F., Cai, Q., Harrison, J. S., Li, L., Wang, Y., Strahl, B. D., Wang, G. G., & Song, J.
- Affiliations
- University of California, Riverside (US)
- Van Andel Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Song, Jikui
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 12
- Issue
- 9
- Pages
- 1400-1406
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4558366
- OpenAlex
- W1751741427
- Cited by
- 99
- References
- 37
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 9 · 2021: 6 · 2020: 12 · 2019: 7 · 2018: 12 · 2017: 14 · 2016: 8 · 2015: 1
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Scholarly Commons (University of the Pacific) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- UNC Libraries
- Funders
- March of Dimes Foundation
- Concern Foundation
- Sidney Kimmel Foundation for Cancer Research
- Debbie's Dream Foundation
- National Institutes of Health (K99-R00, CA181343)
- National Cancer Institute (K99CA181343, R00CA181343, K99CA151683, K99‐R00, R00CA151683, CA151683, K99/R00 CA151683, CA181343)
- National Institute of General Medical Sciences (GM110058, R01GM110058)
- National Institute of Environmental Health Sciences (R01ES019873, ES019873)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- UHRF1, USP7, deubiquitination, allosteric interactions, polybasic region, tandem Tudor domain, chromatin targeting, histone binding, protein complex structure, cell cycle regulation, protein stability
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Allosteric Regulation, Allosteric Site, Amino Acid Sequence, Chromatin, Humans, Molecular Sequence Data, Protein Binding, Protein Transport, CCAAT-Enhancer-Binding Proteins, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
