Cited by 18Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsNF-κB Signaling Pathways

Preferential digestion of PCNA-ubiquitin and p53-ubiquitin linkages by USP7 to remove polyubiquitin chains from substrates.

Open access
Masuda, Yuji, Kanao, Rie, Kawai, Hidehiko, Kukimoto, Iwao, Masutani, Chikahide·2019·Journal of Biological Chemistry

Abstract

Ubiquitin-specific protease 7 (USP7) regulates various cellular pathways through its deubiquitination activity. Despite the identification of a growing number of substrates of USP7, the molecular mechanism by which USP7 removes ubiquitin chains from polyubiquitinated substrates remains unexplored. The present study investigated the mechanism underlying the deubiquitination of Lys 63 -linked polyubiquitinated proliferating cell nuclear antigen (PCNA). Biochemical analyses demonstrated that USP7 efficiently removes polyubiquitin chains from polyubiquitinated PCNA by preferential cleavage of the PCNA-ubiquitin linkage. This property was largely attributed to the poor activity toward Lys 63 -linked ubiquitin chains. The preferential cleavage of substrate-ubiquitin linkages was also observed for Lys 48 -linked polyubiquitinated p53 because of the inefficient cleavage of the Lys 48 -linked ubiquitin chains. The present findings suggest a mechanism underlying the removal of polyubiquitin signals by USP7.

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  • USP7 is inefficient in recycling and converting free-floating polyubiquitin chains to monoubiquitin if the chain is not attached to a substrate.

    “As a means of regulating substrate-specificity, USP7 is inefficient in recycling and converting free-floating polyubiquitin chains to monoubiquitin if the chain is not attached to a substrate (Schaefer and Morgan, 2011; Masuda et al., 2019).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Masuda et al., 2019

  • Biochemical assays suggest USP7 might deubiquitinate PCNA modified by K63-linked ubiquitin chains.

    “Although it is yet to be demonstrated in cells, biochemical assays have suggested USP7 might also be able to deubiquitinate PCNA modified by the addition of K63-linked ubiquitin chains (Masuda et al., 2019).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Masuda et al., 2019

  • This defect seems due to a role of USP7 in regulating ubiquitination of the PCNA sliding clamp.

    “This defect seems due to a role of USP7 in regulating ubiquitination of the PCNA sliding clamp (Kashiwaba et al., 2015; Qian et al., 2015; Masuda et al., 2019).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Masuda et al., 2019

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  • 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

    “As a means of regulating substrate-specificity, USP7 is inefficient in recycling and converting free-floating polyubiquitin chains to monoubiquitin if the chain is not attached to a substrate (Schaefer and Morgan, 2011; Masuda et al., 2019).”
    BackgroundInfluential

Authors
Masuda, Y., Kanao, R., Kawai, H., Kukimoto, I., & Masutani, C.
Affiliations
  • Research Institute of Environmental Medicine, Nagoya University (JP)
  • Hiroshima University (JP)
  • National Institute of Infectious Diseases (JP)
Corresponding author
Masuda, Yuji
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2019-03
Volume
294
Issue
11
Pages
4177-4187
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2910025953
Cited by
18
References
42
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2021: 3 · 2020: 4 · 2019: 2
FWCI
0.74
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • MEXT | Japan Society for the Promotion of Science (15H02818, 18H03371, 16K12594, 18K11638)
  • Ministry of Education, Culture, Sports, Science and Technology (16H01775)
  • Takeda Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
USP7, deubiquitination, PCNA, p53, polyubiquitin chains, ubiquitin linkage specificity, ubiquitin-specific protease, ubiquitination
MeSH terms
Ubiquitin-Specific Peptidase 7, Humans, Substrate Specificity, Ubiquitins, Tumor Suppressor Protein p53, Proliferating Cell Nuclear Antigen

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