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Cited by 114Ubiquitin and proteasome pathwaysCancer-related Molecular PathwaysMicrotubule and mitosis dynamics

USP7 Is a Master Regulator of Genome Stability

Open access
Valles, Gabrielle J., Bezsonova, Irina, Woodgate, Roger, Ashton, Nicholas W.·2020·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2020.00717PMC PMC7419626
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Abstract

Genetic alterations, including DNA mutations and chromosomal abnormalities, are primary drivers of tumor formation and cancer progression. These alterations can endow cells with a selective growth advantage, enabling cancers to evade cell death, proliferation limits, and immune checkpoints, to metastasize throughout the body. Genetic alterations occur due to failures of the genome stability pathways. In many cancers, the rate of alteration is further accelerated by the deregulation of these processes. The deubiquitinating enzyme ubiquitin specific protease 7 (USP7) has recently emerged as a key regulator of ubiquitination in the genome stability pathways. USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression. In this work, we review the increasingly evident role of USP7 in maintaining genome stability, the links between USP7 deregulation and cancer progression, as well as the rationale of targeting USP7 in cancer therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

USP7 is a deubiquitinating enzyme that regulates genome stability through cell cycle, replication, mitosis, telomere, DNA repair, and apoptosis pathways, and its deregulation is linked to cancer progression. This review summarizes USP7 structure, substrates, cancer associations, and the rationale for targeting USP7 with small-molecule inhibitors.

Key findings

  • USP7 is an ∼128 kDa cysteine protease with a TRAF-like domain, catalytic domain (C223, H464, D481), and five UBL domains; it deubiquitinates substrates including p53, Mdm2, Mdm4, MCM-BP, UHRF1, DNMT1, and RNF169, with reported Kd values such as p53 18 ± 1.5 μM, Mdm2 8 ± 0.3 μM, and DNMT1 0.6 ± 0.05 μM.
  • USP7 regulates cell cycle progression, replication, mitosis, telomere maintenance, p53-dependent transcription, nucleotide excision repair, double-strand break repair, DNA damage bypass, and apoptosis; USP7 depletion causes cell cycle defects, chromosomal abnormalities, aneuploidy, and impaired DSB repair.
  • USP7 has context-dependent tumor suppressor and oncogenic roles; low USP7 expression correlated with reduced p53 immunostaining and poor prognosis in non-small cell lung adenocarcinoma, while high USP7 correlated with Geminin, PHF8, and cyclin A2 in breast cancers. Heterozygous loss-of-function USP7 mutations were identified in 23 individuals with neurodevelopmental disorders, and homozygous knockout in mice causes early embryonic lethality.
  • USP7 inhibitors target the catalytic domain, with examples including XL188 (Kd = 90 nM), FT671 (Kd = 65 nM), FT827 (Kd = 7.8 μM), and GNE-6640 (IC50 = 0.43 ± 0.07 μM); no human trials of USP7 inhibitors have yet been conducted, but inhibitors induce p53-dependent apoptosis and sensitize cancer cells to chemotherapy or radiation in preclinical models.

Methods

  • Narrative review; no primary experimental data are presented.
  • Synthesizes published structural, biochemical, and cancer-biology literature, including tables of USP7 substrate interactions with Kd/PDB IDs and USP7 inhibitors with Kd/IC50/PDB IDs.
  • Main analysis is a conceptual synthesis of USP7’s roles in genome stability pathways and its links to cancer therapy.

Limitations

  • No formal limitations section is stated; the text notes unresolved issues including the precise catalog of SUMOylated proteins targeted by USP7, how cells balance opposing USP7 functions, and conflicting findings on DNMT1 stability and Pol η protein levels.
  • Evident from the text: this is a narrative review without systematic search criteria or meta-analysis, and it reports no primary experiments; human trials of USP7 inhibitors have not yet been conducted.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fcell.2020.00717

Cites

272 of 272 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    USP7 is the sole member of the USP family with a TRAF-like domain.

    “Of the USP family of enzymes, USP7 is the sole member with a TRAF-like domain.”
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    No human individuals have been identified who are USP7 homozygous-null.

    “no human individuals have been identified who are USP7 homozygous-null (Fountain et al., 2019)”
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  • Interpretationcitation

    The USP7 TRAF-like domain endows USP7 with unique substrate recognition and specificity that sets it apart from other USPs.

    “This endows USP7 with unique substrate recognition and specificity that sets it apart from other USPs (Nijman et al., 2005).”
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    Truncation of amino acids 1-207 of USP7 abolishes its ability to enter the nucleus.

    “Thus, truncation of amino acids 1–207 abolishes its ability to enter the nucleus.”
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    USP7 regulates the p53/Mdm2 signaling axis.

    “This includes its significant role in genome stability, where USP7 regulates the well-characterized p53/Mdm2 signaling axis (Li et al., 2004)”
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    Premisecitation

    USP7 is deregulated in many cancer types, and deviations in USP7 protein levels are correlated with cancer progression.

    “USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression.”
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    Premisecitation

    Following ubiquitin binding to the catalytic domain, the USP7 C-terminal domains assume a conformation that allows its disordered tail (residues 1084-1102) to bind to the switching loop, promoting an active state and increasing USP7 enzymatic activity.

    “Studies have shown that following ubiquitin binding to the catalytic domain, the USP7 C-terminal domains assume a conformation that allows its disordered tail (residues 1084–1102) to bind to the “switching loop.” This conformational switch promotes an “active” state, increasing USP7 enzymatic activity.”
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    Securin inhibits the protease separase, which cleaves the cohesin rings that hold sister chromatids together to initiate anaphase.

    “Securin, in turn, inhibits the protease separase, which is responsible for cleaving the cohesin rings that hold sister chromatids together to initiate anaphase (Ross and Cohen-Fix, 2002).”
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    Interpretationreasoning

    All USP7 TRAF-like substrate interactions occur on an identical interface, so these interactions occur in a mutually exclusive manner.

    “As all USP7 TRAF-like substrate interactions occur on an identical interface, these interactions occur in a mutually exclusive manner.”
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    Premisecitation

    USP7 specifically cleaves ubiquitin and is unable to cleave other ubiquitin-like modifiers including SUMO and Nedd8.

    “USP7 specifically cleaves ubiquitin and is unable to cleave other ubiquitin-like modifiers including SUMO and Nedd8 (Fernandez-Montalvan et al., 2007).”
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    Interpretationreasoning

    By stabilizing both PLK1 and Bub3, USP7 regulates chromosomal segregation in two ways: by regulating proper attachment of microtubules to kinetochores and by ensuring a proper checkpoint response can be initiated.

    “By stabilizing both PLK1 and Bub3, USP7 therefore regulates chromosomal segregation in two ways: 1) by regulating the proper attachment of microtubules to the kinetochores, and 2) by ensuring a proper checkpoint response can be initiated, in the event of any errors.”
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    Premisecitation

    Bub3 is a key component of the Spindle Assembly Checkpoint (SAC), where it functions with other members of the Mitotic Checkpoint Complex (MCC).

    “Bub3 is a key component of the Spindle Assembly Checkpoint (SAC), where it functions with other members of the Mitotic Checkpoint Complex (MCC) (Musacchio, 2015).”
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    Premisecitation

    The catalytic domains of all USPs possess a characteristic papain-like fold with a "thumb, palm, fingers" sub-domain architecture.

    “Despite differences in size, the catalytic domains of all USPs possess a characteristic papain-like fold with a “thumb, palm, fingers” sub-domain architecture (Reyes-Turcu et al., 2009)”
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    Premisecitation

    The USP7 catalytic domain contains a conserved Cysteine-Histidine box formed by residues C223, H464 and D481.

    “The catalytic domains of USPs contain a highly conserved Cysteine-Histidine box, which in USP7 is formed by residues C223, H464 and D481 (Hu et al., 2001).”
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    Premisecitation

    TPP1 interacts directly with telomerase and is a processivity factor for telomerase-mediated telomere lengthening.

    “In addition, TPP1 interacts directly with telomerase and is a processivity factor for telomerase-mediated telomere lengthening (Wang et al., 2007; Xu et al., 2019).”
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    Premisecitation

    In the apo-enzyme inactive USP7 catalytic domain structure, active site residues are too far apart to perform enzymatic functions, while in the active ubiquitin-bound structure these residues move towards each other.

    “In the apo-enzyme or “inactive” catalytic domain structure, active site residues are too far apart to perform enzymatic functions, while these same residues move towards each other in the “active” ubiquitin-bound structure.”
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    Premisecitation

    Ubiquitin binding does not result in broad conformational changes to the USP7 catalytic domain, but major structural deviations occur for the active site catalytic triad residues C223, H464, D481.

    “Crystal structures of the USP7 catalytic domain apo-enzyme (PDB ID: 1nb8) and the USP7 catalytic domain in complex with ubiquitin-aldehyde (PBD ID: 1nbf), reveal that for the most part, ubiquitin-binding does not result in broad conformational changes to the catalytic domain. However, major structural deviations do occur for the active site catalytic triad residues (C223, H464, D481), which”
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    Premisecitation

    USP7 is unable to cleave methionine-linked linear ubiquitin chains.

    “Like other USPs, USP7 is unable to cleave methionine-linked linear ubiquitin chains (Faesen et al., 2011a).”
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    USP7 TRAF-like domain substrates include p53, Mdm2, Mdm4, and MCM-BP.

    “These substrates include the tumor suppressor p53 (Hu et al., 2006; Sheng et al., 2006), the Mdm2 E3 ubiquitin ligase (Hu et al., 2006; Sheng et al., 2006; Sarkari et al., 2010), the Mdm2 homolog Mdm4 (Sarkari et al., 2010) and mini-chromosome maintenance binding-protein MCM-BP (Jagannathan et al., 2014; Figure 1 and Table 1).”
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    Interpretationreasoning

    By limiting TPP1 degradation, USP7 presumably contributes to the integrity of the telomere cap and to regulation of telomerase-mediated end lengthening.

    “Although a precise functional outcome of USP7-mediated TPP1 stabilization remains unclear, by limiting TPP1 degradation, USP7 presumably contributes to the integrity of telomere cap as well as regulation of telomerase-mediated end lengthening.”
    Quote in the paperSubstantial claim

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    Premisecitation

    USP7 stabilizes human TPP1, likely in conjunction with other DUBs.

    “USP7, however, stabilizes human TPP1, likely in conjunction with other DUBs (Zemp and Lingner, 2014).”
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    Premisecitation

    Ubiquitination of human TPP1 signals the protein for proteasomal degradation, unlike murine TPP1 whose ubiquitination promotes telomere localization.

    “Unlike murine TPP1, whose ubiquitination promotes telomere localization (Rai et al., 2011), the ubiquitination of human TPP1 signals the protein for proteasomal degradation.”
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    Premisecitation

    SIRT1 deacetylase modulates SUV39H1 by deacetylating SUV39H1 K266 and by deacetylating H3K9Ac to allow SUV39H1 methylation.

    “SUV39H1 function is also modulated by the SIRT1 deacetylase, which regulates SUV39H1 in two separate ways: (1) by deacetylating SUV39H1 lysine residue 266 (K266) (Vaquero et al., 2007) and (2) by deacetylating lysine 9 of histone H3 (H3K9Ac) to allow SUV39H1 methylation (Vaquero et al., 2004, 2007).”
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    Premisecitation

    DAXX enhances the interaction between USP7 and Mdm2 and enhances Mdm2 E3 ubiquitin ligase activity towards p53.

    “The interaction between USP7 and Mdm2 is also enhanced by DAXX, which simultaneously binds both proteins and enhances the E3 ubiquitin ligase activity of Mdm2 towards p53 (Tang J. et al., 2006).”
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    Premisecitation

    USP7 deubiquitinates and stabilizes Mdm4 (also known as Mdmx).

    “Furthermore, USP7 deubiquitinates and stabilizes the Mdm2 interacting partner – and substrate (Kawai et al., 2003; Pan and Chen, 2003) – Mdm4 (also known as Mdmx) (Meulmeester et al., 2005).”
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    Premisecitation

    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).”
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    Interpretationcitation

    USP7 can regulate SUV39H1 activity and p53 transcription via SIRT1 stabilization.

    “As SIRT1 was recently found to be deubiquitinated and stabilized by USP7, these findings suggest another way through which USP7 can regulate SUV39H1 activity and p53 transcription (Song et al., 2020).”
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    Premisecitation

    MDC1 is a binding partner of the MRN nuclease complex and functions in the initial detection and signaling of DSBs.

    “MDC1 is a binding partner of the MRN nuclease complex (Goldberg et al., 2003) and functions in the initial detection and signaling of DSBs (Stewart et al., 2003).”
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    Premisecitation

    USP7 interacts with and deubiquitinates the lesion sensing factor XPC.

    “In the former, USP7 has been found to interact with and deubiquitinate the lesion sensing factor, XPC (He et al., 2014).”
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    Interpretationcitation

    USP7 has apparent functions in the initiation steps of both GG-NER and TC-NER pathways.

    “USP7 has apparent functions in the initiation steps of both GG- and TC-NER pathways.”
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    Premisecitation

    Deubiquitination of XPC by USP7 stabilizes XPC and prevents its premature degradation.

    “Deubiquitination of XPC by USP7, however, stabilizes XPC and prevents its premature degradation (He et al., 2014).”
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    Premisecitation

    RNF168 promotes 53BP1 and BRCA1 localization to DSBs, while RNF169 competes with 53BP1 and BRCA1 for ubiquitin binding and inhibits this binding.

    “While RNF168 promotes 53BP1 and BCRA1 localization to sites of DSBs, RNF169 is a direct inhibitor of this binding. This is because, once RNF168 synthesizes H2A/H2AX ubiquitin chains, RNF169 competes with 53BP1 and BRCA1 for ubiquitin binding (Chen et al., 2012; Panier et al., 2012; Poulsen et al., 2012).”
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    Premisecitation

    USP7 directly deubiquitinates and stabilizes RNF168 and its paralog RNF169.

    “In addition to stabilizing MDC1 – and thus promoting RNF168 accumulation – USP7 also directly deubiquitinates and stabilizes RNF168 (Zhu et al., 2015), as well as its paralog, RNF169 (An et al., 2017).”
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    Premisecitation

    53BP1 and BRCA1 promote DSB signaling, and 53BP1 subsequently prevents DSB resection during HR.

    “Although it seems counterintuitive for USP7 to both promote and limit 53BP1 and BRCA1 accumulation at sites of DSBs, an explanation may come from the finding that while 53BP1 and BRCA1 promote DSB signaling, 53BP1 subsequently prevent DSB resection during HR (Bunting et al., 2010; Coleman and Greenberg, 2011).”
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    Premisecitation

    These phosphorylation events disrupt p53-Mdm2 and Mdm2-DAXX interactions and promote degradation of Mdm2 and Mdm4.

    “These phosphorylation events contribute to disrupting the p53-Mdm2 (Chehab et al., 2000; Shieh et al., 2000), and Mdm2-DAXX (Tang et al., 2013) interactions, as well as to the degradation of Mdm2 and Mdm4 (Stommel and Wahl, 2004; Chen et al., 2005; Pereg et al., 2005, 2006; LeBron et al., 2006).”
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    Premisecitation

    RASSF1A disrupts the Mdm2-DAXX-USP7 interaction in response to DNA damage by binding Mdm2 and DAXX, thereby destabilizing Mdm2 and allowing a p53-dependent delay in G1-S progression.

    “The RASSF1A tumor suppressor is one such protein, which disrupts the Mdm2-DAXX-USP7 interaction in response to DNA damage by simultaneously binding to both Mdm2 and DAXX. RASSF1A thereby destabilizes Mdm2, allowing for a p53-dependent delay in G1-S cell cycle progression (Song et al., 2008b).”
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    Premisecitation

    TSPYL5 disrupts the p53-USP7 interaction, leading to increased polyubiquitination and degradation of p53.

    “TSPYL5 disrupts the p53-USP7 interaction, leading to increased polyubiquitination and degradation of p53.”
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    Premisecitation

    ABRO1 stabilizes the p53-USP7 interaction and promotes USP7-mediated p53 deubiquitination.

    “ABRO1 (also known as FAM175B) also contributes to the p53 response by stabilizing the p53-USP7 interaction and promoting USP7-mediated p53 deubiquitination (Zhang J. et al., 2014).”
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    Premisecitation

    In early TC-NER, USP7 interacts with and is recruited to lesions by UVSSA, and this interaction is important for USP7 to localize and stabilize ERCC6.

    “In the early stages of TC-NER, USP7 interacts with and is recruited to lesions by the UVSSA scaffolding protein. This interaction is important for USP7 to localize and subsequently stabilize the adjacent protein, ERCC6 (Schwertman et al., 2012).”
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    Premisecitation

    USP7 has a role in the initial stages of both translesion synthesis and template switching.

    “Recent reports have suggested that USP7 has a role in the initial stages of both translesion synthesis and template switching.”
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    Premisecitation

    USP7 has been proposed to regulate the stability of the TLS polymerase DNA polymerase eta (Pol η).

    “USP7 has also been proposed to regulate the stability of the TLS polymerase, DNA polymerase eta (Pol η) (Qian et al., 2015).”
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    Interpretationreasoning

    USP7 regulates Pol η protein levels both positively by direct deubiquitination and negatively by stabilizing Mdm2.

    “Furthermore, as Pol η is polyubiquitinated by Mdm2 (Jung et al., 2012), which is itself a substrate of USP7 (Li et al., 2004), these observations suggest that USP7 regulates Pol η protein levels both positively (by direct deubiquitination) and negatively (by stabilizing Mdm2).”
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    Premisecitation

    Depleting USP7 decreases protein levels of Rad18 and HLTF, suppresses PCNA mono- and polyubiquitination, and reduces Pol η foci formation in UV irradiated cells.

    “Indeed, depleting USP7 from cells was found to decrease the protein levels of Rad18 and HLTF, suppress PCNA mono and polyubiquitination, as well as reduce Pol η foci formation in UV irradiated cells.”
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    Premisecitation

    Pro-apoptotic Bcl-2 family members (e.g., PUMA, Bax) mediate mitochondrial outer membrane permeabilization and caspase activation.

    “This includes pro-apoptotic members of the Bcl-2 family (e.g., PUMA, Bax), which mediate mitochondrial outer membrane permeabilization and subsequent caspase activation, to dismantle the cell (Nakano and Vousden, 2001; Chipuk et al., 2004; Aubrey et al., 2018).”
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    Interpretationreasoning

    USP7 may act to balance the level of HLTF by promoting both polyubiquitination via CHFR and deubiquitination of HLTF.

    “USP7 may therefore act to balance the level of HLTF in the cell, by promoting both polyubiquitination (via CHFR) and deubiquitination of the protein.”
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    Premisecitation

    ZEB1 enhances the interaction between USP7 and Chk1 and is phosphorylated and stabilized by ATM in response to DNA damage.

    “Here, the interaction between USP7 and Chk1 is enhanced by ZEB1, which is itself phosphorylated and stabilized by the ATM kinase, in response to DNA damage (Zhang P. et al., 2014).”
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    Premisecitation

    USP7 seems to regulate Pol η transcriptionally via p53 and through protein stabilization by directly removing K48-linked polyubiquitin chains.

    “Here, USP7 seems to regulate Pol η transcriptionally – via p53 (Lerner et al., 2017) – as well as through protein stabilization by directly removing K48-linked polyubiquitin chains.”
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    Premisecitation

    Both depletion and over-expression of USP7 in cells were reported to enhance Pol η protein levels.

    “Indeed, as evidence of this complexity, both the depletion and over-expression of USP7 in cells were reported to enhance Pol η protein levels (Qian et al., 2015).”
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    Premisecitation

    Acetylation of p53 K120 by Kat5 increases its binding affinity for Bax and PUMA promoters and prevents binding to the p21 promoter.

    “K120 resides within the p53 DNA-binding domain and its acetylation increases its binding affinity for the Bax and PUMA gene promoters, while simultaneously preventing binding to the promoter of p21 (Sykes et al., 2006; Tang Y. et al., 2006; Reed and Quelle, 2014).”
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    • cites Reed and Quelle, 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During translesion synthesis, PCNA is monoubiquitinated at K164 by Rad18, stimulating recruitment of TLS polymerases.

    “During translesion synthesis, the PCNA sliding clamp is monoubiquitinated at lysine residue 164 (K164) by the E3 ubiquitin ligase, Rad18 (Watanabe et al., 2004). This modification stimulates recruitment of translesion synthesis polymerases, which bind the PCNA ubiquitin group via their ubiquitin-binding domains (Kannouche et al., 2004; Bienko et al., 2005).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Watanabe et al., 2004 source

      Not checked in the free run.

    • cites Kannouche et al., 2004 source

      Not checked in the free run.

    • cites Bienko et al., 2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    XL188 in complex with the USP7 catalytic domain binds about 5 Å from the catalytic triad.

    “The inhibitor in complex with the USP7 catalytic domain reveals that binding occurs about 5 Å from the catalytic triad (Lamberto et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lamberto et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FT671 in complex with the USP7 catalytic domain is several angstroms from C223, similar to XL188.

    “The non-covalent inhibitor FT671 in complex with the catalytic domain reveals this inhibitor is several angstroms from C223, similar to XL188.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Turnbull et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High-throughput screening led to the development of non-covalent pyrimidone-based inhibitors including Compounds 2 and 5.

    “High-throughput screening led to the development of non-covalent pyrimidone-based inhibitors, including Compounds 2 and 5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gavory et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Similar chromosomal abnormalities were detected in both p53 positive and null cell lines following USP7 depletion, suggesting this phenotype might be caused by means other than p53 deregulation.

    “Although p53 status was not a reported parameter in these analyses, similar chromosomal abnormalities were detected in both p53 positive and null cell lines following USP7 depletion, suggesting this phenotype might be caused by means other than p53 deregulation (Giovinazzi et al., 2013, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Giovinazzi et al., 2013 source

      Not checked in the free run.

    • cites Giovinazzi et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Compound 46 is a non-covalent pyrimidine-based USP7 inhibitor.

    “Similarly, the non-covalent pyrimidine-based USP7 inhibitor Compound 46 binds a few angstroms from the active site residues (O’Dowd et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O’Dowd et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7 deubiquitinates and stabilizes PHF8, allowing PHF8 to upregulate gene targets involved in cell cycle progression, including cyclin A2.

    “As we discussed in the Cell Cycle Regulation section, USP7 deubiquitinates and stabilizes PHF8, allowing the latter to upregulate gene targets involved in cell cycle progression, including cyclin A2 (Liu et al., 2010; Wang et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Liu et al., 2010 source

      Not checked in the free run.

    • cites Wang et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    USP7 has context-dependent tumor suppressor and oncogenic roles, and up- or down-regulation can contribute to carcinogenesis.

    “Together, these data demonstrate that USP7 has context-dependent tumor suppressor and oncogenic roles and that up- or down-regulation can contribute to carcinogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ki-67 is highly expressed in malignant tissues and promotes cell division.

    “As with Cyclin A2, Ki-67 is highly expressed in malignant tissues and promotes cell division (Sales Gil and Vagnarelli, 2018; Horie et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sales Gil and Vagnarelli, 2018

      Not checked in the free run.

    • cites Horie et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both USP7-FT inhibitor complexes reveal a misaligned catalytic triad and the switching loop in an unproductive conformation.

    “Despite differences in binding, both USP7-FT inhibitor complexes reveal a misaligned catalytic triad and the switching loop being in an unproductive conformation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Turnbull et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High Geminin protein levels are prognostic of poor clinical outcome and are associated with genome instability, DNA replication errors and aneuploidy.

    “High Geminin protein levels are prognostic of poor clinical outcome and are associated with genome instability, DNA replication errors and aneuploidy (Sundara Rajan et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sundara Rajan et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Compound 46 binds a few angstroms from the active site residues of USP7.

    “Similarly, the non-covalent pyrimidine-based USP7 inhibitor Compound 46 binds a few angstroms from the active site residues (O’Dowd et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O’Dowd et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7 gene expression is frequently downregulated in non-small cell lung adenocarcinomas, where low USP7 mRNA expression correlated with reduced p53 immunostaining.

    “Consistent with this assessment, USP7 gene expression has been found to be frequently downregulated in non-small cell lung adenocarcinomas, where low USP7 mRNA expression correlated with reduced p53 immunostaining (Masuya et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Masuya et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Compounds 2 and 5 both bind over 5 Å away from C223.

    “These compounds both bind over 5 Å away from C223 (Gavory et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gavory et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7, PHF8 and cyclin A2 were all found to be upregulated in several breast cancers, as well as in colon and rectum cancers, compared to adjacent tissues.

    “Indeed, USP7, PHF8 and cyclin A2 were all found to be upregulated in several breast cancers, as well as in colon and rectum cancers, compared to adjacent tissues (Wang et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FT827 in complex with the USP7 catalytic domain enters the active site cleft and covalently modifies C223.

    “Inhibitor FT827 in complex with the catalytic domain reveals that this inhibitor enters the active site cleft and covalently modifies C223.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Turnbull et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7 contributes to p53-dependent apoptosis by interacting with and deubiquitinating Kat5, and promotes p53 K120 acetylation, PUMA expression, and apoptosis following DNA damage.

    “In addition to stabilizing p53 protein levels, USP7 contributes to p53-dependent apoptosis through interacting with and de-ubiquitinating Kat5. Further, USP7 was found to promote p53 K120 acetylation, as well as PUMA expression and apoptosis following DNA damage (Dar et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dar et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Taxanes kill cancer cells by binding to and stabilizing β-tubulin on the inner surface of microtubules, increasing their polymerization.

    “Taxanes, such as paclitaxel and docetaxel, kill cancer cells by binding to and stabilizing β-tubulin on the inner surface of microtubules, increasing their polymerization (Jordan et al., 1993).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jordan et al., 1993 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutation of C223 to alanine prevents inhibitor binding to USP7, revealing specificity for the catalytic cysteine.

    “Here, mutation of C223 to an alanine prevents inhibitor binding to USP7, revealing specificity for the catalytic cysteine (Pozhidaeva et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pozhidaeva et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    USP7 Inhibitor 2, part of the GNE-inhibitor screen, binds distal to the catalytic site.

    “USP7 Inhibitor 2, which was part of the GNE-inhibitor screen, also binds distal to the catalytic site (Di Lello et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Di Lello et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Taxanes prevent proper chromosome orientation on the metaphase plate, leading to activation of the spindle-assembly checkpoint and stalling cells at the metaphase to anaphase transition.

    “Taxanes, in this way, prevent proper chromosome orientation on the metaphase plate, leading to activation of the spindle-assembly checkpoint and stalling cells at the metaphase to anaphase transition (Musacchio and Salmon, 2007; Gascoigne and Taylor, 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Musacchio and Salmon, 2007

      Not checked in the free run.

    • cites Gascoigne and Taylor, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Taxane binding prevents proper mitotic cell division, as disruption to microtubule dynamics precludes proper tension across sister chromatids.

    “This binding prevents proper mitotic cell division, as although chromosomes can be attached to taxane-stabilized microtubules, the disruption to microtubule dynamics precludes proper tension being established across sister chromatids (Kelling et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kelling et al., 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7 is upregulated in many cervical carcinomas, where its expression positively correlates with MDC1 and histological tumor grade.

    “For instance, USP7 has been found to be upregulated in many cervical carcinomas, where its expression positively correlates with that of MDC1, as well as with histological tumor grade.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Su et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of USP7 with GNE-6640 or GNE-6776 destabilizes MDC1 and sensitizes cervical cancer cells to ionizing radiation-induced genotoxic insult.

    “Inhibition of USP7 with the compounds GNE-6640 or GNE-6776, however, destabilizes MDC1, as well as sensitizes cervical cancer cells to ionizing radiation-induced genotoxic insult (Su et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Su et al., 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A new class of GNE cyanopyrrolidine-based inhibitors has been described.

    “Recently, a new class of GNE cyanopyrrolidine-based inhibitors has been described.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bashore et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    USP7 inhibitor HBX 19,818 specifically and covalently targets C223 with low micromolar affinity.

    “USP7 inhibitor HBX 19,818 also specifically and covalently targets C223 with low micromolar affinity (Reverdy et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Reverdy et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    USP7 IC50 for P50429 and P22077 are in the low micromolar range.

    “While the USP7 IC50 for P50429 and P22077 are in the low micromolar range, these inhibitors are not specific to USP7 as they also target the USP7 homolog USP47 (Tian et al., 2011; Weinstock et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Tian et al., 2011 source

      Not checked in the free run.

    • cites Weinstock et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    P22077 and P50429, derivatives of 5091, both irreversibly modify C223.

    “P22077 and P50429, also derivatives of 5091, both irreversibly modify C223.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pozhidaeva et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Paclitaxel and docetaxel are front-line chemotherapeutics for treating breast, prostate and nasopharyngeal carcinomas.

    “While paclitaxel and docetaxel are front-line chemotherapeutics for treating breast, prostate and nasopharyngeal carcinomas, resistance to these compounds often develops (Murray et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Murray et al., 2012 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    These findings suggest another prospective use for USP7 inhibitors in cancer treatment.

    “These findings suggest another prospective use for USP7 inhibitors in cancer treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    By inducing PLK1 degradation, USP7 inhibition with P5091 sensitizes taxane-resistant cancer cells to paclitaxel and docetaxel and triggers apoptotic cell death.

    “By inducing PLK1 degradation, USP7 inhibition with P5091 was, however, found to sensitize taxane-resistant cancer cells to paclitaxel and docetaxel and to trigger apoptotic cell death (Peng et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Peng et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    USP7 and PLK1 were found to correlate in tissue sections of primary breast cancer and to be highly expressed in taxane-resistant tumors.

    “Indeed, USP7 and PLK1 were found to correlate in tissue sections of primary breast cancer and to be highly expressed in taxane-resistant tumors (Peng et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Peng et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    USP7 has become an attractive pharmacological target for inducing apoptotic cell death in cancer cells.

    “Recently, USP7 has become an attractive pharmacological target for inducing apoptotic cell death in cancer cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Improper activity of USP7 leads to destabilization of its many substrates, resulting in genetic alterations that may drive tumorigenesis.

    “Improper activity of USP7 leads to destabilization of its many substrates, resulting in genetic alterations that may drive tumorigenesis.”
    Quote in the paperNot a substantial claim
78 of 78

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?

  • Backtracking of RNAPII allows correction of misincorporated nucleotides in RNA:DNA hybrids within transcription bubbles via cleavage of 3′ protruding RNA parts with mismatched nucleotides.

    “Moreover, backtracking of RNAPII allows correction of misincorporated nucleotides in RNA:DNA hybrids within transcription bubbles via cleavage of 3′ protruding RNA parts with mismatched nucleotides.”

    From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [102]

  • This event may be promoted by transcription factor TFIIS, which acts as a stimulator of RNAPII mRNA-cleavage activity.

    “This event may be promoted by transcription factor TFIIS that acts as a stimulator of RNAPIIs mRNA-cleavage activity.”

    From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [102]

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Related

Authors
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W.
Affiliations
  • UConn Health (US)
  • National Institutes of Health (US)
Corresponding author
  • Woodgate, Roger
  • Ashton, Nicholas W.
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2020-08-05
Volume
8
Pages
717-717
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2020.00717
PMC
PMC7419626
OpenAlex
W3047549203
Semantic Scholar
db11de8d45fae0f60cc23111c12319234809bb0e
Cited by
114
References
274
Citations by year
2026: 17 · 2025: 24 · 2024: 23 · 2023: 21 · 2022: 17 · 2021: 11 · 2020: 1
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R35 GM128864, P41 GM111135, R01 GM123249)
  • National Science Foundation (1616184)
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 › Cell Biology › Microtubule and mitosis dynamics
Keywords
USP7, genome stability, deubiquitination, ubiquitination, tumor progression, chromosomal instability, DNA mutations, targeted cancer therapy, tumor suppression

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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.

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