Affinage

USP37

Ubiquitin carboxyl-terminal hydrolase 37 · UniProt Q86T82

Length
979 aa
Mass
110.2 kDa
Annotated
2026-06-11
46 papers in source corpus 34 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP37 is a cell cycle- and stress-regulated deubiquitinase that controls the stability and activity of numerous regulatory proteins by reversing their ubiquitylation, coupling proteostasis to proliferation, DNA replication, and the DNA damage response (PMID:21596315, PMID:40379725). Its catalytic output is gated by phosphorylation—CDK2 stimulates full deubiquitinase activity in S phase, while CDK1 phosphorylation at Thr631 further enhances activity (PMID:21596315, PMID:40486858)—and by three internal ubiquitin-interacting motifs (UIMs); UIMs 2 and 3 bind ubiquitinated substrates and ubiquitin chains, with the third UIM recognizing the proximal ubiquitin of K48 chains to raise catalytic rate without imposing chain-type specificity (PMID:24324262, PMID:30858488). USP37 abundance is itself periodically controlled: it antagonizes APC(CDH1) by stripping K11-linked chains from cyclin A before switching to an APC(CDH1) substrate in late mitosis, and it is degraded at G2/M by SCF(βTrCP) in a Plk1-phosphorylation-dependent manner (PMID:21596315, PMID:23027877). At the replisome, USP37 binds CDC45 within the CMG helicase through its Pleckstrin-Homology domain and deubiquitinates MCM7, counteracting CMG ubiquitylation by CUL2LRR1 and TRAIP to prevent premature replisome disassembly and sustain replication under stress (PMID:40411782, PMID:40533495, PMID:40379725); it further stabilizes CHK1, limits RPA and HLTF accumulation at stalled forks, and supports CDT1-dependent origin licensing (PMID:34509474, PMID:40548939, PMID:27296872). In the DNA damage response, USP37 removes RNF168-induced conjugates at double-strand breaks to promote homologous recombination, and ATM- and CHK2-directed phosphorylation enhances its binding to and stabilization of BLM helicase and FOXO4, the latter promoting senescent-cell survival (PMID:26101254, PMID:34606619, PMID:41980094). USP37 also resolves sister chromatids by deubiquitinating chromatin-associated WAPL (PMID:26299517). Through these activities USP37 stabilizes an array of growth-promoting and oncogenic factors—c-Myc, HIF2α, Snail1, Gli-1, β-catenin, ERα, p27, and SAMHD1—linking it to proliferation, EMT, stemness, and viral restriction across multiple cancer contexts (PMID:25284584, PMID:32461361, PMID:31911859, PMID:30482232, PMID:37424824, PMID:36221793, PMID:22665064, PMID:39655951).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2011 High

    Establishing USP37 as a deubiquitinase that opposes APC(CDH1) defined its core biochemical activity and embedded it in cell cycle control.

    Evidence Co-IP, ubiquitin chain-type mass spectrometry, and in vivo deubiquitination of cyclin A with CDK2 phospho-site mutagenesis in cell-cycle assays

    PMID:21596315

    Open questions at the time
    • Did not resolve how CDK2 phosphorylation mechanistically activates the catalytic domain
    • Other substrates beyond cyclin A unaddressed
  2. 2012 High

    Identifying SCF(βTrCP)/Plk1-driven degradation showed USP37 levels are oscillated to permit the G2/M transition, complementing its APC(CDH1) regulation.

    Evidence Co-IP, Plk1 phospho-site mutagenesis, and chemical/genetic Plk1 inhibition with synchronization and flow cytometry

    PMID:23027877

    Open questions at the time
    • Did not map all relevant Plk1 sites
    • Functional consequences of stabilized mutant beyond G2/M delay limited
  3. 2012 High

    Discovery that USP37 stabilizes the CDK inhibitor p27 and the PLZF/RARA fusion revealed both growth-suppressive and oncogenic outputs and introduced REST as a transcriptional repressor of USP37.

    Evidence Co-IP, catalytic Cys mutants, CHX chase, domain mapping, and primary hematopoietic progenitor transformation assays

    PMID:22665064 PMID:23208507

    Open questions at the time
    • Context determinants of whether USP37 favors p27 versus oncogenic substrates not defined
    • Direct chain-type on p27/PLZF-RARA not characterized
  4. 2013 High

    Defining the three UIMs explained how USP37 engages ubiquitinated substrates and showed UIMs 2/3 enhance catalysis without conferring chain-type specificity.

    Evidence UIM point mutagenesis, in vitro K48/K63 chain binding, in-cell isopeptidase assays, and localization imaging

    PMID:24324262

    Open questions at the time
    • Structural basis of UIM-catalytic domain coupling not resolved
    • Role of UIM1 left unclear
  5. 2014 High

    Identification of c-Myc as a stabilized substrate connected USP37 to proliferative and metabolic (Warburg) reprogramming, and HBx hijacking of USP37 linked it to viral oncogenesis.

    Evidence Co-IP, in vivo deubiquitination, DUB-activity-dependent stabilization assays, and HBx co-localization/stability analyses

    PMID:25284584 PMID:25347529

    Open questions at the time
    • HBx study (Medium) lacks full mechanistic reconstitution of relocalization
    • Ubiquitin chain type on c-Myc not defined
  6. 2015 High

    Three converging studies placed USP37 at DNA double-strand breaks, on the cohesin/WAPL axis, and on additional substrates, establishing genome-maintenance and mitotic roles.

    Evidence Genetic/RNAi screens, epistasis (RAP80 double depletion, HR reporter), Co-IP, catalytic C350A mutant, and in vitro deubiquitination of purified WAPL

    PMID:26101254 PMID:26299517 PMID:26427597

    Open questions at the time
    • Recruitment mechanism of USP37 to DSBs not defined
    • 14-3-3γ regulation (Medium) lacks mechanistic depth
  7. 2016 Medium

    Linking USP37 to CDT1 stabilization and MCM loading connected it to origin licensing and replication fork speed, foreshadowing a direct replisome role.

    Evidence Overexpression screen, Co-IP, in vivo deubiquitination, and chromatin loading/fork speed assays

    PMID:27296872

    Open questions at the time
    • Phospho-form preference of CDT1 not biochemically dissected
    • Direct versus indirect effect on MCM loading unresolved
  8. 2017 Medium

    Defining REST/G9a-mediated epigenetic repression of the USP37 promoter explained how USP37 expression is silenced and validated it as a therapeutic node in medulloblastoma.

    Evidence ChIP at the USP37 promoter, pharmacologic and genetic G9a perturbation, and orthotopic mouse model

    PMID:28483947

    Open questions at the time
    • Generality of G9a regulation beyond medulloblastoma untested
    • Other transcriptional inputs not surveyed
  9. 2018 Medium

    Identification of Gli-1 stabilization tied USP37 to hedgehog-driven stemness, EMT, and invasion in cancer stem cells.

    Evidence Co-IP, MG132/CHX chase, immunofluorescence, and KD with stemness/invasion readouts plus xenograft

    PMID:30482232

    Open questions at the time
    • Direct deubiquitination of Gli-1 not reconstituted in vitro
    • Mechanism of Smo decrease unclear
  10. 2019 High

    Establishment of Snail1 as a directly stabilized substrate, plus kinetic dissection of the third UIM and UbV inhibitors, deepened both the EMT link and the druggability of USP37.

    Evidence Co-IP, catalytic mutants (C350S), migration epistasis, and in vitro kinetic assays with UIM mutants and ubiquitin-variant inhibitors

    PMID:30858488 PMID:31911859

    Open questions at the time
    • In vivo efficacy of UbV inhibitors untested
    • Selectivity of inhibitors across DUBs not established
  11. 2020 High

    Demonstrating HIF2α stabilization in clear cell renal carcinoma and Snail1 stabilization in lung cancer extended USP37's oncogenic substrate repertoire to hypoxia and metastasis programs.

    Evidence DUB cDNA library binding screen, Co-IP, enzymatic-mutant deubiquitination, orthotopic xenograft, and migration epistasis

    PMID:31998374 PMID:32461361

    Open questions at the time
    • How USP37 selects HIF2α over other substrates unclear
    • Lung Snail1 study (Medium) overlaps prior work without new mechanism
  12. 2021 High

    DNA damage and replication-stress studies showed phosphorylation-gated stabilization of BLM and CHK1, linking USP37 kinase inputs (ATM) to DSB repair and checkpoint signaling.

    Evidence Co-IP, in vivo deubiquitination, ATM kinase assay, CHK1 stability/S-phase kinetics, and DNA-damage sensitization assays; PLAGL2-USP37-Snail1 transcriptional axis

    PMID:33391500 PMID:34509474 PMID:34606619

    Open questions at the time
    • ATM phospho-sites on USP37 not all mapped here
    • Coordination between CHK1 and BLM stabilization unaddressed
  13. 2022 Medium

    Identification of CDC73/parafibromin stabilization and TOP2a-driven transcriptional activation in neural stem cells broadened USP37's substrate and regulatory landscape into chromatin and self-renewal.

    Evidence Yeast two-hybrid, Co-IP, domain mapping, K48-specific deubiquitination, and RNA-seq/ChIP-seq with conditional knockout rescue

    PMID:35742816 PMID:36029179

    Open questions at the time
    • Physiological role of CDC73 deubiquitination beyond stability untested
    • TOP2a-USP37 axis function outside NSCs unknown
  14. 2023 Medium

    Showing ERα and β-catenin stabilization placed USP37 within estrogen-responsive and Wnt-driven oncogenic programs.

    Evidence Co-IP, K48-specific ubiquitination assays, ERE-luciferase reporter, epistasis rescue, and xenograft

    PMID:36221793 PMID:37424824

    Open questions at the time
    • β-catenin study lacks in vitro deubiquitination reconstitution
    • Direct versus pathway-level effects not fully separated
  15. 2025 High

    Two independent structural/biochemical studies established USP37 as a bona fide replisome-associated DUB that binds CDC45 within CMG and deubiquitinates MCM7 to oppose CUL2LRR1/TRAIP-driven replisome disassembly.

    Evidence AlphaFold-Multimer modeling, structure-guided mutagenesis, Co-IP, genetic epistasis (CUL2LRR1/TRAIP depletion), Xenopus CMG ubiquitylation assay, RNAi screen, proteomics, and chromatin fractionation

    PMID:40379725 PMID:40411782 PMID:40533495

    Open questions at the time
    • Trigger that activates USP37 at terminating versus stressed forks unclear
    • Coordination with CDC45 binding and catalytic timing not fully resolved
  16. 2025 Medium

    Functional fork studies and new substrate/phosphorylation findings extended USP37 into RPA/HLTF regulation at stalled forks, CDK1-Thr631 activation, FOXO4-driven senescent survival, and additional oncogenic substrates.

    Evidence Whole-genome CRISPR screen, Co-IP, in vivo deubiquitination, HLTF epistasis, CDK1/CHK2 kinase assays with phospho-site mutagenesis, and pharmacological inhibitor (dacarbazine) validation

    PMID:39655951 PMID:40486858 PMID:40548939 PMID:41408466 PMID:41980094

    Open questions at the time
    • Substrate selectivity governing the many reported targets not unified
    • Some substrate claims (Medium) rest on single-lab studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single deubiquitinase achieves selectivity across its very broad reported substrate set—and which targets dominate in defined physiological versus disease contexts—remains unresolved.
  • No unifying determinant of substrate choice beyond UIM/phospho-gating established
  • Relative in vivo importance of replisome versus transcription-factor substrates unquantified
  • Low-confidence substrates (SALL4, NRF2) lack reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-69306 DNA Replication 5 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 1
Partners
BLMCDC45CDH1CHK1FOXO4MCM7RPAWAPL
Complex memberships
APC/C (transient substrate/antagonist)CMG replicative helicasecohesin complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 USP37 binds CDH1 (APC/C adaptor) and removes degradative K11-linked polyubiquitin from cyclin A, antagonizing APC(CDH1)-mediated degradation. USP37 is phosphorylated by CDK2, which stimulates its full deubiquitinase activity. In late mitosis, USP37 switches from an APC(CDH1) antagonist to an APC(CDH1) substrate and is itself modified with K11-linked polyubiquitin for degradation. Co-immunoprecipitation, ubiquitin chain-type mass spectrometry, in vivo deubiquitination assay, overexpression/knockdown cell-cycle analysis, phospho-site mutagenesis Molecular cell High 21596315
2012 USP37 is degraded at the G2/M transition by the SCF(βTrCP) E3 ligase in a phosphorylation-dependent manner mediated by Polo-like kinase 1 (Plk1). Mutation of Plk1 phospho-sites on USP37 abolishes βTrCP binding and renders USP37 resistant to degradation; expression of this stabilized mutant hinders the G2/M transition. Co-immunoprecipitation, phospho-site mutagenesis, chemical/genetic Plk1 inhibition, cell-cycle synchronization and flow cytometry The Journal of biological chemistry High 23027877
2012 USP37 forms a complex with p27 (CDKN1B), deubiquitinates and stabilizes p27, thereby limiting cell proliferation. A catalytic cysteine mutant of USP37 fails to rescue p27 stabilization, confirming that enzymatic activity is required. REST transcription factor represses USP37 expression to destabilize p27 and maintain proliferation in medulloblastoma cells. Co-immunoprecipitation, in vivo deubiquitination assay, site-directed mutagenesis (catalytic Cys), knockdown/overexpression with proliferation and protein-stability readouts Oncogene High 22665064
2012 USP37 interacts with the PLZF/RARA fusion protein through the PLZF moiety (N-terminal domain of USP37 required) and deubiquitinates PLZF/RARA, stabilizing it. Overexpression increases and depletion decreases PLZF/RARA half-life; knockdown of Usp37 alleviates PLZF/RARA-mediated target gene suppression and cell transformation in primary mouse hematopoietic progenitors. Co-immunoprecipitation, domain mapping, ubiquitination assay, RNAi screen, CHX chase, primary cell transformation assay Oncogene High 23208507
2013 USP37 contains three ubiquitin-interacting motifs (UIMs) between its Cys and His boxes. UIMs 2 and 3 are required for binding to ubiquitinated proteins and to both K48- and K63-linked ubiquitin chains in vitro. Mutation of UIM2 or UIM3 significantly reduces USP37 isopeptidase activity toward ubiquitinated substrates without affecting nuclear localization, indicating UIMs enhance catalytic efficiency without conferring chain-type specificity. UIM point-mutation analysis, in vitro ubiquitin-chain binding, in-cell isopeptidase activity assays, nuclear localization imaging The Journal of biological chemistry High 24324262
2014 USP37 directly binds and deubiquitinates c-Myc, stabilizing it and preventing proteasomal degradation. Overexpression of USP37 increases c-Myc levels; depletion promotes c-Myc degradation. Stabilization requires USP37 deubiquitinase activity (DUB activity-dependent manner), and USP37 regulates cell proliferation and the Warburg effect through c-Myc levels. Co-immunoprecipitation, in vivo deubiquitination assay, USP overexpression screen, knockdown/overexpression with protein stability and functional readouts Oncogene High 25284584
2014 HBx oncoprotein of hepatitis B virus directly interacts with USP37 (Co-IP and confocal co-localization), promotes translocation of USP37 out of the nucleus, and prevents its ubiquitination by APC/CDH1 and SCF/βTrCP. This stabilizes USP37, which in turn deubiquitinates cyclin A, deregulating the cell cycle. Co-immunoprecipitation, confocal microscopy, flow cytometry, ubiquitination assay, protein stability analysis PloS one Medium 25347529
2015 USP37 (and USP26) are recruited to DNA double-strand breaks where they remove RNF168-induced ubiquitin conjugates. Depletion of USP37 disrupts homologous recombination (HR); this defect is rescued by simultaneous RAP80 depletion (epistasis). USP37 prevents excessive spreading of the RAP80-BRCA1 complex from DSBs while promoting BRCA1 interaction with PALB2. Genetic screen, siRNA knockdown, epistasis (double depletion rescue), imaging of DSB-recruited factors, HR reporter assay Nucleic acids research High 26101254
2015 USP37 associates with the cohesin complex and with WAPL (a negative regulator of cohesion) via its second and third UIMs. USP37 deubiquitinates WAPL in vitro (catalytically dead C350A mutant inactive), stabilizes chromatin-associated WAPL, and is required for sister chromatid resolution and mitotic progression. Depletion causes centrosome and chromosome alignment defects. RNAi screen, Co-immunoprecipitation (WAPL, cohesin), catalytic mutant (C350A), in vitro deubiquitination with purified USP37, flow cytometry/imaging Current biology : CB High 26299517
2015 USP37 regulates the stability of 14-3-3γ through its catalytic deubiquitinase activity, preventing its ubiquitin-mediated degradation. Interaction between USP37 and 14-3-3γ was identified by screening and confirmed biochemically. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression Oncotarget Medium 26427597
2016 USP37 interacts with and deubiquitinates Cdt1 in vivo, preferentially stabilizing a phosphorylated form of Cdt1 during G1 and G1/S. USP37 knockdown reduces MCM complex loading onto chromatin and slows DNA replication fork speed. Overexpression screen, Co-immunoprecipitation, in vivo deubiquitination, knockdown with MCM chromatin loading and fork speed assays Molecular oncology Medium 27296872
2017 USP37 expression is transcriptionally repressed by REST through G9a histone methyltransferase-mediated H3K9 mono-, di-, and trimethylation at the USP37 promoter. Genetic or pharmacologic inhibition of G9a de-represses USP37 in medulloblastoma cells and blocks tumor growth in vivo. ChIP assay, G9a pharmacologic inhibition, genetic G9a knockdown, isogenic REST cell lines, orthotopic mouse model Molecular cancer research : MCR Medium 28483947
2018 USP37 interacts with and stabilizes Gli-1 (hedgehog pathway effector) in breast cancer stem cells via deubiquitination. Knockdown of USP37 decreases Smo and Gli-1 levels and inhibits stemness, EMT, and cell invasion via the Hh pathway. Co-immunoprecipitation, MG132 treatment, CHX chase, immunofluorescence, knockdown/overexpression with stemness and invasion readouts, in vivo xenograft Journal of experimental & clinical cancer research : CR Medium 30482232
2019 USP37 directly binds, deubiquitinates, and stabilizes SNAI1 (Snail1). Overexpression of wild-type but not catalytically inactive C350S mutant promotes cancer cell migration; depletion of USP37 downregulates SNAI1 and suppresses migration, rescued by SNAI1 re-expression. Co-immunoprecipitation, in vivo deubiquitination, catalytic mutant (C350S), knockdown/overexpression with migration assay and epistasis American journal of cancer research High 31911859
2019 The third UIM of USP37 recognizes the proximal ubiquitin moiety of K48-linked di-ubiquitin chains to potentiate cleavage activity, primarily through an increase in catalytic rate (kcat). Three ubiquitin variant (UbV) inhibitors were developed that selectively engage distinct binding sites (including the three UIMs) in USP37 and inhibit its activity. In vitro deubiquitination kinetics with UIM mutants, UbV inhibitor characterization, binding assays Scientific reports High 30858488
2020 USP37 is co-localized with Snail in the nucleus and deubiquitinates Snail, preventing its proteasomal degradation and promoting lung cancer cell migration. Depletion of Snail abolishes the pro-migratory effect of USP37. Co-immunoprecipitation, immunofluorescence co-localization, knockdown epistasis, migration assay Frontiers in genetics Medium 31998374
2020 USP37 binds HIF2α and promotes its deubiquitination in an enzymatically dependent manner, stabilizing HIF2α protein in clear cell renal cell carcinoma. Depletion of USP37 decreases HIF2α levels, reduces proliferation and anchorage-independent growth, and suppresses orthotopic kidney tumor growth and lung metastasis. DUB cDNA library binding screen, Co-immunoprecipitation, in vivo deubiquitination, enzymatic mutant, MTS/colony/3D growth assays, orthotopic xenograft Proceedings of the National Academy of Sciences of the United States of America High 32461361
2021 PLAGL2 transcriptionally activates USP37, which then interacts with and deubiquitinates Snail1, stabilizing it. GSK-3β-dependent phosphorylation of Snail1 is required for USP37-mediated Snail1 deubiquitination. Transcriptional reporter assay, Co-immunoprecipitation, in vivo deubiquitination, phosphorylation analysis, in vitro and in vivo tumor models Theranostics Medium 33391500
2021 USP37 interacts with and deubiquitinates BLM helicase, stabilizing it. DNA double-strand breaks promote ATM-mediated phosphorylation of USP37, which enhances USP37-BLM binding. USP37 knockdown increases BLM polyubiquitination, accelerates proteolysis, impairs DDR, and sensitizes breast cancer cells to DNA-damaging agents. Co-immunoprecipitation, in vivo deubiquitination, ATM kinase assay, knockdown with γH2AX/DNA damage readouts, in vivo mouse model Nucleic acids research High 34606619
2021 USP37 deubiquitinates and stabilizes checkpoint kinase 1 (CHK1), promoting its activity and the cellular response to replication stress. USP37-depleted cells exhibit increased γH2AX and 53BP1 upon perturbed replication, reduced CHK1 levels, altered S-phase kinetics, and increased sensitivity to replication stress agents. Flow cytometry, microscopy with thymidine analog labeling, in vivo deubiquitination, CHK1 stability assay, knockdown with replication stress agents The Journal of biological chemistry Medium 34509474
2022 USP37 deubiquitinates CDC73/parafibromin via K48-linked ubiquitin chain removal, stabilizing it. The β-catenin binding site of CDC73 and UIMs 2 and 3 of USP37 mediate their interaction. The catalytically inactive USP37(C350S) mutant fails to deubiquitinate CDC73. Both proteins co-localize in the nucleus. Yeast two-hybrid, Co-immunoprecipitation, domain mapping, in vivo deubiquitination, catalytic mutant (C350S), co-localization imaging International journal of molecular sciences Medium 35742816
2022 TOP2a directly activates Usp37 transcription in adult neural stem cells (NSCs) of the subventricular zone (SVZ), as identified by RNA-seq and ChIP-seq. Overexpression of Usp37 rescues the impaired self-renewal of adult NSCs caused by Top2a knockdown. RNA-seq, ChIP-seq, conditional knockout, overexpression rescue in adult NSCs Nucleic acids research Medium 36029179
2023 USP37 interacts with ERα and stabilizes it by inhibiting K48-specific polyubiquitination, without affecting ERα gene expression. USP37 depletion decreases ERα protein levels, reduces ERα target gene expression and estrogen response element activity, and causes cell cycle arrest in ERα-positive breast cancer cells, rescued by ERα overexpression. Co-immunoprecipitation, in vivo ubiquitination assay, knockdown/overexpression epistasis, ERE-luciferase reporter, flow cytometry Cancer science Medium 36221793
2023 USP37 enhances β-catenin stability by inhibiting its ubiquitination in colorectal cancer cells. USP37 silencing suppresses β-catenin levels and the angiogenic, metastatic, and stemness phenotypes of CRC cells. Co-immunoprecipitation, ubiquitination assay, knockdown with functional readouts (proliferation, invasion, angiogenesis), in vivo xenograft American journal of cancer research Medium 37424824
2024 USP37 interacts with and deubiquitinates SAMHD1, reversing Vpx- and TRIM21-mediated K48-linked polyubiquitination and degradation of SAMHD1. USP37's deubiquitinase activity and UIMs are required for SAMHD1 deubiquitination; USP37 phosphorylation state does not affect this activity. USP37 stabilization of SAMHD1 enhances restriction of HIV-2/SIV replication and LINE-1 retrotransposition. Co-immunoprecipitation, in vivo deubiquitination assay, catalytic mutant, UIM mutant, viral replication assay, LINE-1 retrotransposition assay Journal of virology Medium 39655951
2025 USP37 binds the CDC45-MCM-GINS (CMG) replisome helicase via its Pleckstrin-Homology Domain contacting CDC45. Structure-guided mutations displacing USP37 from CMG phenocopy loss of catalytic activity. USP37 counteracts CMG ubiquitylation by CUL2LRR1, which induces replisome disassembly during termination; CUL2LRR1 depletion suppresses Usp37-mutant sensitivity to DNA synthesis defects and ATR inhibitors. TRAIP mutation specifically suppresses Usp37-mutant sensitivity to topological stress. Structural modeling (AlphaFold-Multimer), structure-guided mutagenesis, Co-immunoprecipitation, genetic epistasis (CUL2LRR1 and TRAIP depletion), Xenopus egg extract CMG ubiquitylation assay Cell reports High 40411782 40533495
2025 USP37 interacts with the CMG complex and deubiquitinates MCM7, antagonizing replisome disassembly. USP37 maintains active replisomes on S-phase chromatin and promotes normal cell cycle progression; loss of USP37 sensitizes cells to replication stress. Targeted RNAi screen, quantitative single-cell analysis, proteomics, biochemical deubiquitination assay, chromatin fractionation Nature communications High 40379725
2025 USP37 deubiquitinates replication protein A (RPA) at stalled replication forks to limit excessive RPA accumulation and progressive RPA exhaustion, preventing conversion of RPA-coated ssDNA to DSBs. USP37 also limits HLTF accumulation at forks to prevent MRE11-dependent fork degradation; HLTF depletion rescues replication damage in USP37 knockout cells. Whole-genome CRISPR screen, Co-immunoprecipitation, in vivo deubiquitination (RPA), genetic epistasis (HLTF depletion), replication fork assays Nucleic acids research Medium 40548939
2025 CDK1 phosphorylates USP37 at Thr631 (not Ser628), enhancing its deubiquitinase activity. USP37 is the deubiquitinase of SND1, stabilizing SND1 and driving colorectal cancer proliferation and metastasis. Dacarbazine was identified as a pharmacological inhibitor of USP37 that disrupts SND1 stability. Proteomics, ubiquitinomics, interactomics, phospho-site mutagenesis, in vitro kinase assay, high-throughput virtual screening with experimental validation Acta pharmaceutica Sinica. B Medium 40486858
2025 USP37 interacts with and deubiquitinates FOXO4 via removal of K48-linked polyubiquitin chains, stabilizing FOXO4 in senescent cells. CHK2 phosphorylates USP37 at Thr589 in response to persistent DNA damage response signaling, enhancing USP37 binding to FOXO4. Depletion of USP37 destabilizes FOXO4 and sensitizes senescent cells to apoptosis, rescued by FOXO4 re-expression. Deubiquitinase screen, Co-immunoprecipitation, in vivo deubiquitination (K48-chain specific), CHK2 kinase assay, phospho-site mutagenesis, knockdown/overexpression epistasis, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 41980094
2025 USP37 deubiquitinates and stabilizes both Raptor (mTORC1 component) and GLI1 (SHH pathway effector) in medulloblastoma cells. Under low-USP37 conditions, reduced Raptor stability decreases mTORC1 activity and increases 4EBP1-eIF4E interaction, inhibiting CAP-dependent translation. USP37-mediated GLI1 stabilization drives CCND1 expression and cell proliferation. Biochemical co-immunoprecipitation, protein stability assays, knockdown/overexpression with mTORC1 signaling and SHH pathway readouts, genetic and biochemical analyses Oncogene Medium 41408466
2025 USP37 interacts with and deubiquitinates SALL4, stabilizing it and activating PI3K/AKT pathway signaling in keloid fibroblasts. USP37 knockdown reduces SALL4 and PI3K/AKT activity; SALL4 overexpression reverses the inhibitory effects of USP37 knockdown. Co-immunoprecipitation, western blot stability assay, PI3K inhibitor epistasis, knockdown/overexpression functional assays Scientific reports Low 40038378
2025 USP37 stabilizes NRF2 through enzymatic activity-dependent deubiquitination. USP37 interacts with NRF2; knockdown leads to increased NRF2 degradation and enhanced cellular sensitivity to chemotherapy in HCC. Co-immunoprecipitation, in vivo deubiquitination, knockdown with NRF2 stability and chemosensitivity readouts Discover oncology Low 40080254

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry. Molecular cell 135 21596315
2014 USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 134 25284584
2018 Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity. Journal of experimental & clinical cancer research : CR 87 30482232
2021 PLAGL2 promotes the proliferation and migration of gastric cancer cells via USP37-mediated deubiquitination of Snail1. Theranostics 64 33391500
2015 The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic acids research 64 26101254
2020 USP37 Promotes Lung Cancer Cell Migration by Stabilizing Snail Protein via Deubiquitination. Frontiers in genetics 53 31998374
2020 USP37 promotes deubiquitination of HIF2α in kidney cancer. Proceedings of the National Academy of Sciences of the United States of America 48 32461361
2012 Skp1-Cul1-F-box ubiquitin ligase (SCF(βTrCP))-mediated destruction of the ubiquitin-specific protease USP37 during G2-phase promotes mitotic entry. The Journal of biological chemistry 42 23027877
2012 The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation. Oncogene 39 22665064
2012 The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability. Oncogene 38 23208507
2016 USP37 deubiquitinates Cdt1 and contributes to regulate DNA replication. Molecular oncology 37 27296872
2015 The Deubiquitinase USP37 Regulates Chromosome Cohesion and Mitotic Progression. Current biology : CB 35 26299517
2021 USP37 regulates DNA damage response through stabilizing and deubiquitinating BLM. Nucleic acids research 34 34606619
2017 Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation. Molecular cancer research : MCR 32 28483947
2015 Deubiquitinating enzyme USP37 regulating oncogenic function of 14-3-3γ. Oncotarget 26 26427597
2013 Ubiquitin-interacting motifs confer full catalytic activity, but not ubiquitin chain substrate specificity, to deubiquitinating enzyme USP37. The Journal of biological chemistry 26 24324262
2014 The HBx oncoprotein of hepatitis B virus deregulates the cell cycle by promoting the intracellular accumulation and re-compartmentalization of the cellular deubiquitinase USP37. PloS one 23 25347529
2021 Intermittent hypoxia-induced downregulation of microRNA-320b promotes lung cancer tumorigenesis by increasing CDT1 via USP37. Molecular therapy. Nucleic acids 19 33898105
2019 USP37 is a SNAI1 deubiquitinase. American journal of cancer research 16 31911859
2022 Topoisomerase IIA in adult NSCs regulates SVZ neurogenesis by transcriptional activation of Usp37. Nucleic acids research 14 36029179
2019 The ubiquitin interacting motifs of USP37 act on the proximal Ub of a di-Ub chain to enhance catalytic efficiency. Scientific reports 14 30858488
2021 miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37. Cancer research and treatment 13 34352998
2021 The deubiquitinating enzyme USP37 enhances CHK1 activity to promote the cellular response to replication stress. The Journal of biological chemistry 13 34509474
2023 Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer. Cancer science 9 36221793
2021 USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin. International journal of medical sciences 9 33390801
2025 CDK1-mediated phosphorylation of USP37 regulates SND1 stability and promotes oncogenesis in colorectal cancer. Acta pharmaceutica Sinica. B 6 40486858
2023 USP37 promotes angiogenesis and metastasis in colorectal cancer by facilitating β-catenin stability. American journal of cancer research 6 37424824
2022 USP37 Deubiquitinates CDC73 in HPT-JT Syndrome. International journal of molecular sciences 5 35742816
2022 The deubiquitinating enzyme USP37 promotes keloid fibroblasts proliferation and collagen production by regulating the c-Myc expression. International wound journal 5 36333840
2025 USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP. Cell reports 4 40411782
2024 Deubiquitinase USP37 enhances the anti-HIV-2/SIV ability of the host restriction factor SAMHD1. Journal of virology 4 39655951
2025 USP37-stabilized SALL4 promotes the keloid formation by PI3K/AKT pathway. Scientific reports 3 40038378
2025 USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination. Nature communications 3 40379725
2025 USP37 prevents premature disassembly of stressed replisomes by TRAIP. Nature communications 3 40533495
2024 USP37 prevents premature disassembly of stressed replisomes by TRAIP. bioRxiv : the preprint server for biology 3 39282314
2023 Investigating In Situ Expression of c-MYC and Candidate Ubiquitin-Specific Proteases in DLBCL and Assessment for Peptidyl Disruptor Molecule against c-MYC-USP37 Complex. Molecules (Basel, Switzerland) 3 36985413
2025 USP37 counteracts HLTF to protect damaged replication forks and promote survival of BRCA1-deficient cells and PARP inhibitor resistance. Nucleic acids research 2 40548939
2025 USP37 as a novel regulator of NRF2 protein stability and chemoresistance in HCC. Discover oncology 1 40080254
2025 Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells. Oncogene 1 41408466
2024 Ubiquitin specific peptidase (USP37) mediated effects in microscaffold-encapsulated cells: a comprehensive study on growth, proliferation and EMT. RSC advances 1 38352690
2024 USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination. bioRxiv : the preprint server for biology 1 39282338
2026 The Smarcal1-Usp37 locus modulates glycogen aggregation in astrocytes of the aged hippocampus. Cell systems 0 41633365
2026 CHK2-USP37 axis stabilizes FOXO4 to sustain senescence and evade apoptosis. Proceedings of the National Academy of Sciences of the United States of America 0 41980094
2025 The CENPN/STAT3/USP37 signaling axis promotes invasion, migration and metastasis in nasopharyngeal carcinoma. Frontiers in oncology 0 40458725
2025 An integrative pan-cancer analysis of USP37 and functional validation in pancreatic cancer. Frontiers in cell and developmental biology 0 40926837
2024 USP37 promotes diffuse large B-cell lymphoma progression by deubiquitinating and stabilizing c-myc. Journal of molecular histology 0 39722070

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