Affinage

TOPORS

E3 ubiquitin-protein ligase Topors · UniProt Q9NS56

Length
1045 aa
Mass
119.2 kDa
Annotated
2026-06-10
57 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOPORS is a dual-function nuclear E3 ligase that conjugates both ubiquitin and SUMO-1 to substrates, thereby coupling SUMO signaling to proteasomal turnover and chromatin regulation (PMID:15247280, PMID:16122737). Its ubiquitin ligase activity depends on an intact RING domain and a conserved tryptophan, and operates through the E2 enzymes UbcH5a, UbcH5c, and UbcH6 (PMID:15247280), whereas its SUMO-1 ligase activity is RING-independent (PMID:16122737). This bifunctionality is integrated at the level of individual targets: on p53, TOPORS can both stabilize the protein through SUMOylation and drive its proteasomal degradation through ubiquitination, with the balance set by phosphorylation (PMID:15247280, PMID:16122737, PMID:19473992). The mature mechanistic model casts TOPORS as a SUMO1-selective SUMO-targeted ubiquitin ligase (STUbL) that recognizes poly-SUMO1 chains via SUMO-interacting motifs and complements the SUMO2/3-selective RNF4, the two acting in parallel on distinct SUMO chains to build the polyubiquitin signal that recruits p97/VCP and triggers degradation; combined loss of TOPORS and RNF4 is synthetic lethal due to failed clearance of SUMOylated chromatin proteins (PMID:38649616, PMID:40239066). Through this activity TOPORS ubiquitinates SUMOylated DNA-protein crosslinks, most notably DNMT1-DPCs formed after hypomethylating-agent treatment, promoting their RING-dependent resolution—a dependency exploited therapeutically in leukemia (PMID:38760575, PMID:39198401, PMID:39198387). TOPORS also SUMOylates RAD51 at K57 and K70 downstream of ATM-mediated phosphorylation of TOPORS T515, promoting RAD51 chromatin loading, BRCA2 association, and homologous recombination repair (PMID:35061896). Additional substrates include NKX3.1, which it targets for proteasomal degradation (PMID:18077445), topoisomerase I and Sin3A, which it poly-SUMOylates (PMID:17803295, PMID:17976381). TOPORS localizes to PML nuclear bodies via its basic C-terminal region in a PML-dependent manner (PMID:12083797) and to centrosomes and photoreceptor connecting-cilium basal bodies (PMID:21159800, PMID:26872363), and its activities are temporally controlled by Plk1 phosphorylation at S718 (PMID:19473992). Loss-of-function studies link TOPORS to pericentric heterochromatin integrity, chromosome segregation, and 3D chromatin compartmentalization (PMID:20429939, PMID:32113985). Haploinsufficiency and truncating TOPORS mutations cause autosomal dominant retinitis pigmentosa (RP31) (PMID:17924349).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 Medium

    Before any enzymatic role was known, the question was whether TOPORS had intrinsic nucleic-acid activity; demonstrating Zn2+-dependent sequence-specific DNA binding established it as a nuclear factor capable of chromatin association.

    Evidence Immunofluorescence, Zn2+-dependent DNA-binding assay, deletion mapping and consensus identification for LUN/TOPORS

    PMID:11278651

    Open questions at the time
    • No demonstrated transcriptional output from this DNA-binding consensus in vivo
    • Relationship between DNA binding and later-defined ligase activities unresolved
  2. 2002 High

    The subnuclear address of TOPORS was unknown; localization to PML nuclear bodies dependent on PML and on a basic C-terminal region, with drug-induced relocalization, placed TOPORS at the SUMO/PML hub and mapped the targeting determinant.

    Evidence GFP live imaging, PML+/+ vs PML-/- MEFs, domain deletion, DRB and camptothecin treatment

    PMID:12083797

    Open questions at the time
    • Functional consequence of PML-body residence not addressed at this stage
    • Mechanism of camptothecin-induced relocalization unexplained
  3. 2003 High

    Whether TOPORS itself is SUMO-regulated was untested; identifying K560 as a SUMO-1 acceptor and UBC9/SUMO-1 interactions showed TOPORS is a SUMO substrate, foreshadowing its embedding in the SUMO machinery.

    Evidence Yeast two-hybrid, co-transfection immunoblot, YFP-SUMO-1 colocalization, K560 mutagenesis

    PMID:14516784

    Open questions at the time
    • Functional role of TOPORS auto-SUMOylation undefined (not required for localization)
    • Did not establish TOPORS as a SUMO ligase itself
  4. 2004 High

    The catalytic identity of TOPORS was open; reconstitution showed RING-dependent ubiquitin ligase activity with defined E2 selectivity and p53 as a degradation substrate, defining its first enzymatic function.

    Evidence In vitro ubiquitination with E2 panel, RING tryptophan mutagenesis, cellular overexpression with proteasome inhibitor; Drosophila ortholog ubiquitinating Hairy with genetic epistasis

    PMID:14871887 PMID:15247280

    Open questions at the time
    • In vivo physiological substrate repertoire not yet defined
    • Did not reconcile p53 degradation with later p53-stabilizing observations
  5. 2005 High

    It was unclear whether TOPORS had a second catalytic activity; demonstrating RING-independent SUMO-1 ligase activity toward p53 (and DJ-1), with opposing effects on p53 stability and transcription, established TOPORS as a dual ubiquitin/SUMO ligase.

    Evidence Reconstituted in vitro SUMO-1 assays, RING-deletion mutants, co-IP, transcriptional reporters, mouse Topors p53 stabilization studies

    PMID:15703819 PMID:15735665 PMID:16122737

    Open questions at the time
    • How a single enzyme reconciles ubiquitination-driven degradation and SUMOylation-driven stabilization of p53 not yet resolved
    • Physiological switch between the two activities unknown
  6. 2007 High

    The substrate breadth and chromatin role were unclear; identifying Sin3A and demonstrating poly-SUMO-1 chain formation on TOP1 broadened the SUMO-ligase function toward chromatin and topoisomerase regulation.

    Evidence Proteomic substrate screen, transfection sumoylation of Sin3A, reconstituted poly-SUMO-1 chain assay on TOP1 with mutant mapping

    PMID:17803295 PMID:17976381

    Open questions at the time
    • No in vitro reconstitution for Sin3A SUMOylation
    • Downstream fate of poly-SUMO-1 chains not yet linked to ubiquitin/degradation
  7. 2007 Medium

    Whether TOPORS dysfunction causes human disease was unknown; positional cloning tied haploinsufficiency-causing mutations to autosomal dominant retinitis pigmentosa (RP31), establishing a Mendelian phenotype.

    Evidence Positional cloning, mutation sequencing, immunolocalization to PML-associated speckles; NKX3.1 ubiquitination/degradation in parallel cancer study

    PMID:17924349 PMID:18077445

    Open questions at the time
    • Molecular basis of retinal-specific vulnerability not explained by haploinsufficiency alone
    • Connection between p53/NKX3.1 ligase activity and retinal degeneration unclear
  8. 2008 High

    How the two ligase activities are independently regulated was unknown; phosphorylation at S98 selectively stimulating ubiquitin ligase activity and E2 binding without affecting SUMO activity showed the activities are separable post-translational switches.

    Evidence Mass spectrometry, S98A/S98D mutants, in vitro ubiquitination, co-IP with UbcH5a

    PMID:19053840

    Open questions at the time
    • Kinase responsible for S98 phosphorylation not identified
    • Physiological trigger for this modification unknown
  9. 2009 High

    The cell-cycle control of TOPORS activity was undefined; Plk1 phosphorylation at S718 was shown to flip TOPORS from p53-SUMOylation toward p53-ubiquitination/degradation and to govern TOPORS turnover and mitotic progression.

    Evidence In vivo phosphorylation, S718A mutant, p53 stability/ubiquitination/sumoylation assays; nocodazole and siRNA mitotic phenotyping

    PMID:19473992 PMID:19821153

    Open questions at the time
    • Mechanism by which one phosphorylation toggles between two enzymatic outputs not structurally defined
    • Mitotic substrates other than p53 not identified
  10. 2010 High

    The cellular and organismal consequences of TOPORS loss were unclear; knockout MEFs revealed roles in chromosome segregation and pericentric heterochromatin, while zebrafish silencing tied TOPORS to ciliary/photoreceptor outer-segment formation with human-mRNA rescue.

    Evidence Topors knockout mouse MEFs, FISH aneuploidy, HP1alpha localization, satellite RT-PCR, HDAC inhibitor sensitivity; zebrafish morpholino with rescue and basal-body localization

    PMID:20429939 PMID:21159800

    Open questions at the time
    • Molecular substrate underlying heterochromatin and segregation defects not identified
    • Mechanistic link between nuclear ligase activity and ciliary basal-body function unresolved
  11. 2012 Medium

    Additional substrates and cytoplasmic partners were sought; TOPORS was shown to ubiquitinate H2AX (with stress-dependent dissociation) and to bind the syndecan-1 cytoplasmic domain required for growth inhibition, extending its reach to DNA-damage histones and membrane signaling.

    Evidence Co-IP, in vitro H2AX ubiquitination, stability assays, oxidative-stress dissociation; yeast two-hybrid, deletion mapping and siRNA for syndecan-1

    PMID:22912899 PMID:22972498

    Open questions at the time
    • H2AX work limited to single lab without reciprocal stress validation
    • Syndecan-1/TOPORS axis mechanism downstream of binding not defined
  12. 2016 Medium

    How TOPORS connects to the degradation machinery and to its disease-relevant localization was unclear; interaction with the proteasomal ATPase PSMC1 and co-localization at the centrosome linked TOPORS physically to the proteasome at a structure relevant to RP.

    Evidence Retinal cDNA yeast two-hybrid, reciprocal co-IP, immunofluorescence co-localization in RPE1 and 661W cells

    PMID:26872363

    Open questions at the time
    • Functional consequence of TOPORS-PSMC1 interaction at the centrosome untested
    • Single lab; not connected to specific substrate degradation
  13. 2020 Medium

    Whether TOPORS shapes genome architecture was unknown; knockdown altering A/B compartmentalization, TAD boundaries, lamina interactions and accessibility tied TOPORS to 3D chromatin organization linked to PML domains.

    Evidence Hi-C, ATAC-seq, ChIP-seq, RNA-seq after Topors knockdown in mouse hepatocytes

    PMID:32113985

    Open questions at the time
    • Direct molecular mediator of architectural changes not identified
    • Causality versus secondary effect of PML-body disruption unresolved
  14. 2022 High

    Whether TOPORS participates in HR repair was open; mapping ATM-dependent T515 phosphorylation and TOPORS-mediated RAD51 SUMOylation at K57/K70 promoting chromatin loading and BRCA2 association placed TOPORS in the damage-induced HR pathway, alongside an immune transcriptional role at the SMAR1 promoter.

    Evidence In vivo SUMOylation, RAD51 and TOPORS site mutants, HR assay, BRCA2 co-IP, chromatin fractionation; ChIP and TLR4-TRIF/LPS analysis for SMAR1

    PMID:34689394 PMID:35061896

    Open questions at the time
    • Whether RAD51 SUMOylation is followed by STUbL-type ubiquitination not addressed here
    • Generality of the SMAR1 transcriptional axis beyond macrophages untested
  15. 2024 High

    The unifying biochemical logic was unresolved; defining TOPORS as a SUMO1-selective STUbL that complements RNF4, with synthetic lethality and substrate specificity for SUMOylated DNMT1-DPCs resolved RING-dependently, established its core mechanism and therapeutic vulnerability.

    Evidence Genome-scale CRISPR screens, in vitro ubiquitination, SIM mapping, p97 recruitment, double-knockout synthetic lethality; proximity proteomics and RING-mutant DNMT1-DPC resolution; xenograft HMA-synergy with DDR readout

    PMID:38649616 PMID:38760575 PMID:39198387 PMID:39198401

    Open questions at the time
    • Full in vivo SUMO1-targeted substrate landscape not enumerated
    • Determinants of SUMO1- versus SUMO2/3-chain selectivity at structural level not fully defined
  16. 2025 High

    How SUMO-isoform selectivity directs TOPORS recruitment in cells was unclear; PML-mutant reconstitution showed TOPORS is recruited only with sufficient SUMO1 conjugation and acts in parallel with RNF4 on distinct chains to drive p97-dependent PML degradation, while a SUMOylation/TOP1 role and a USP7-TOPORS-BRCA1-A axis extend its regulation.

    Evidence PML-/- reconstitution with WT/A216T/L217F mutants and arsenic; SUMO1-TOP1 IP in stressed macrophages; quantitative proteomics after USP7 inhibition (preprint)

    PMID:40239066 PMID:40532862 PMID:bio_10.1101_2025.01.28.635372

    Open questions at the time
    • USP7-TOPORS-BRCA1-A axis rests on a preprint without direct co-IP validation
    • Structural basis of SUMO1-selective chain recognition still incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how TOPORS's nuclear STUbL biochemistry mechanistically produces its retinal-ciliary disease phenotype, i.e. which substrate(s) at the photoreceptor basal body underlie RP31.
  • No retinal-specific TOPORS substrate identified
  • Link between centrosomal/basal-body localization and STUbL activity unresolved
  • Why haploinsufficiency manifests selectively in photoreceptors unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 9 GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2 GO:0005654 nucleoplasm 2 GO:0005815 microtubule organizing center 2 GO:0005929 cilium 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-73894 DNA Repair 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2
Partners
BRCA2PMLPSMC1RAD51RNF4SDC1TP53USP7
Complex memberships
PML nuclear bodies

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TOPORS functions as a RING domain-dependent E3 ubiquitin ligase in vitro, utilizing E2 enzymes UbcH5a, UbcH5c, and UbcH6 (but not UbcH7, CDC34, or UbcH2b), and ubiquitinates p53 both in vitro and in cells; a conserved tryptophan in the RING domain is required for ubiquitination activity; overexpression leads to proteasome-dependent decrease in p53 protein levels. In vitro ubiquitination assay, RING domain mutagenesis, cellular overexpression with proteasome inhibition The Journal of biological chemistry High 15247280
2005 TOPORS acts as a SUMO-1 E3 ligase for p53, enhancing SUMO-1 conjugation to p53 both in vivo and in a reconstituted in vitro system; this SUMO-1 E3 ligase activity does not require the RING finger motif; in HeLa cells, Topors-induced p53 sumoylation was accompanied by increased endogenous p53 protein levels. Reconstituted in vitro SUMO-1 conjugation assay, cellular co-transfection, RING finger deletion mutants FEBS letters High 16122737
2005 DJ-1 binds TOPORS/p53BP3 in vitro and in vivo; TOPORS mediates sumoylation of both p53 and DJ-1 in cells; TOPORS-mediated sumoylation of p53 abrogates p53 transcriptional activity in a dose-dependent manner; DJ-1 restores repressed p53 transcriptional activity by releasing the sumoylated form of p53. Co-IP, in vitro binding assay, co-localization, transcriptional reporter assay, cellular sumoylation assay International journal of oncology Medium 15703819
2002 Topors localizes to promyelocytic leukemia (PML) nuclear bodies in a PML-dependent manner; the basic C-terminal region (not the RING domain) is required for punctate nuclear localization; topors dynamically relocalizes from nuclear bodies to the nucleoplasm upon treatment with transcription inhibitor DRB or the topoisomerase I-targeting drug camptothecin. GFP fusion live imaging, fractionation, isogenic PML+/+ vs PML-/- MEFs, domain deletion analysis, drug treatment Experimental cell research High 12083797
2003 TOPORS is itself a SUMO-1 modification target; it interacts with SUMO-1 and the SUMO-1 conjugating enzyme UBC9 in yeast two-hybrid; multiple SUMO-1 modified forms of Topors are detected after co-transfection; lysine 560 within the central domain (residues 437–574) is a SUMO-1 acceptor site; sumoylation-deficient mutants show that sumoylation is not required for localization to nuclear speckles. Yeast two-hybrid, co-transfection and immunoblot, YFP-SUMO-1 colocalization, site-directed mutagenesis Experimental cell research High 14516784
2004 Drosophila Topors (dTopors) functions as an E3 ubiquitin-protein isopeptide ligase in vitro and mediates polyubiquitination and degradation of the Hairy transcriptional repressor; dTopors binds specifically to the basic region of Hairy but does not affect Hairy's DNA binding; reducing dtopors gene dose genetically antagonizes Hairy-mediated transcriptional repression. In vitro ubiquitination assay with recombinant dTopors, genetic dose reduction (epistasis), co-immunoprecipitation The Journal of biological chemistry High 14871887
2005 Mouse topors associates with and stabilizes p53, enhances p53-dependent transcriptional activities (p21Waf1, MDM2, Bax promoters), elevates endogenous p21Waf1 mRNA, and overexpression suppresses cell growth by cell cycle arrest and/or apoptosis; topors expression is induced by genotoxic agents cisplatin and camptothecin. Co-IP, transcriptional reporter assays, RT-PCR, cell growth/apoptosis assays, overexpression Oncogene Medium 15735665
2007 TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins; proteomic screen identified candidate substrates involved in chromatin modification/transcriptional regulation; mammalian Sin3A was confirmed as a sumoylation substrate for TOPORS by transfection studies. Proteomic screen, transfection-based sumoylation assay Journal of proteome research Medium 17803295
2007 TOPORS enhances formation of high-molecular-weight SUMO-1 conjugates (poly-SUMO-1 chains) on DNA topoisomerase I (TOP1) in a reconstituted in vitro system and in human osteosarcoma cells; TOP1 point mutants suggest chains form on a limited number of SUMO-1 acceptor sites. Reconstituted in vitro SUMO-1 conjugation assay, cellular overexpression, TOP1 point mutant analysis FEBS letters High 17976381
2007 TOPORS mutations (insertion and deletion causing haploinsufficiency) cause autosomal dominant retinitis pigmentosa (RP31); TOPORS localizes in the nucleus in speckled loci associated with PML bodies; lack of mutant protein in patients suggests haploinsufficiency as disease mechanism. Positional cloning, mutation identification by sequencing, immunolocalization American journal of human genetics Medium 17924349
2007 TOPORS ubiquitinates the prostate tumor suppressor NKX3.1 in vitro and in vivo; overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells; siRNA knockdown of TOPORS increases steady-state NKX3.1 levels and prolongs its half-life. In vitro ubiquitination assay, cellular overexpression, siRNA knockdown, cycloheximide chase The Journal of biological chemistry High 18077445
2008 Phosphorylation of serine 98 (adjacent to the RING domain) regulates TOPORS ubiquitin ligase activity: S98D (phosphomimetic) increases ubiquitin ligase activity and binding to E2 enzyme UbcH5a both in vitro and in cells; this phosphorylation does not affect SUMO ligase activity or punctate nuclear localization. Multiple phosphorylated regions were identified by mass spectrometry. Mass spectrometry, site-directed mutagenesis (S98A, S98D), in vitro ubiquitination assay, co-IP with E2 Biochemistry High 19053840
2009 Plk1 phosphorylates Topors on Ser718 in vivo; expression of Plk1-unphosphorylatable Topors (S718A) leads to dramatic p53 accumulation through inhibition of p53 degradation; Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53 while enhancing p53 ubiquitination, leading to p53 degradation. In vivo phosphorylation assay, site-directed mutagenesis (S718A), p53 stability assay, ubiquitination and sumoylation assays The Journal of biological chemistry High 19473992
2009 Plk1-associated phosphorylation of Topors at S718 is essential for nocodazole-induced degradation of Topors; Topors depletion delays mitotic entry and affects mitotic progression, implicating Topors in normal mitotic progression. Spindle checkpoint activation (nocodazole), siRNA knockdown, phosphorylation analysis Molecular biology reports Medium 19821153
2010 TOPORS localizes to the basal bodies of the connecting cilium in photoreceptors and to centrosomes in cultured cells; morpholino-mediated silencing of topors in zebrafish results in defective retinal development and failure to form outer segments, phenotypes rescued by mRNA encoding human TOPORS. Immunolocalization in retinal sections, morpholino knockdown in zebrafish, mRNA rescue experiment Human molecular genetics High 21159800
2010 Topors-deficient mouse embryonic fibroblasts exhibit increased malignant transformation associated with aneuploidy and defective chromosomal segregation; Topors-deficient cells show mislocalization of HP1alpha and increased transcription from pericentric major satellite DNA, indicating altered pericentric heterochromatin; these cells are resistant to anti-proliferative effects of the HDAC inhibitor trichostatin A. Topors knockout mouse, MEF transformation assay, FISH for aneuploidy, HP1alpha immunolocalization, RT-PCR of satellite DNA, HDAC inhibitor treatment BMC molecular biology High 20429939
2012 TOPORS interacts with H2AX and functions as an E3 ubiquitin ligase for H2AX in vitro; TOPORS overexpression decreases H2AX protein stability; TOPORS dissociates from H2AX under oxidative stress (hydrogen peroxide, ionizing radiation) but not under replication-stress-inducing damage. Co-IP from mammalian cell extracts, in vitro ubiquitination assay, overexpression stability assay, stress-dependent dissociation analysis Journal of biochemical and molecular toxicology Medium 22972498
2012 Syndecan-1 cytoplasmic domain (S1CD) interacts with Topors via a specific 18-amino acid sequence of Topors identified by deletion mutagenesis; Topors and Sdc-1 co-localize near the cell periphery; siRNA knockdown of Topors demonstrates Topors is required for the inhibitory effect of Sdc-1 on cell growth and PDGF-B induction in arterial smooth muscle cells. Yeast two-hybrid, ligand blotting, co-precipitation, deletion mutagenesis, immunohistochemistry, siRNA knockdown PloS one Medium 22912899
2016 TOPORS interacts with the 26S protease regulatory subunit 4 (P26s4/PSMC1), an ATPase component of the proteasome; interaction validated by yeast two-hybrid, co-immunoprecipitation from mammalian cells, and immunofluorescent co-localization; TOPORS and P26s4 co-localize at the centrosome in cultured hTERT-RPE1 and 661W cells. Yeast two-hybrid screen of human retinal cDNA library, co-IP from mammalian cells, immunofluorescence co-localization PloS one Medium 26872363
2020 TOPORS knockdown in mouse hepatocytes increases chromatin interactions between A and B compartments, reduces compartmentalization strength, weakens TAD boundaries at A/B borders, decreases chromatin-lamina interactions (LAD coverage from 53.31% to 46.52%), and alters chromatin accessibility predominantly at intergenic regions including enhancers; these changes are associated with PML nuclear bodies and PML-associated domains. Hi-C, ATAC-seq, ChIP-seq, RNA-seq after Topors knockdown in mouse hepatocytes Biochimica et biophysica acta. Gene regulatory mechanisms Medium 32113985
2022 TOPORS mediates SUMOylation of RAD51 at lysine residues K57 and K70 in response to DNA damage; this SUMOylation is facilitated by ATM-induced phosphorylation of TOPORS at threonine 515; SUMOylation-deficient RAD51 mutants exhibit reduced chromatin loading and HR repair efficiency, and reduced association with BRCA2. In vivo SUMOylation assay, site-directed mutagenesis of RAD51 (K57R, K70R), phosphorylation analysis of TOPORS T515, HR repair assay, co-IP with BRCA2, chromatin fractionation Nucleic acids research High 35061896
2022 TOPORS binds the SMAR1 promoter (confirmed by ChIP) and its occupancy increases upon LPS treatment; TOPORS is induced via the TLR4-TRIF pathway by LPS; TOPORS-mediated transcriptional upregulation of SMAR1 subsequently represses STAT3 and shifts tumor-associated macrophage polarization toward M1 phenotype. ChIP analysis, siRNA knockdown, LPS treatment, macrophage polarization assay Molecular oncology Medium 34689394
2024 TOPORS functions as a SUMO-targeted ubiquitin ligase (STUbL), combining RING domain-mediated ubiquitin ligase activity with poly-SUMO binding via SUMO-interacting motifs; TOPORS is SUMO1-selective and complements RNF4 (which is SUMO2/3-selective) in generating complex ubiquitin landscapes on SUMOylated targets including DNA-protein crosslinks (DPCs) and PML, stimulating p97/VCP recruitment and proteasomal degradation; combined loss of TOPORS and RNF4 is synthetic lethal in unstressed cells due to defective clearance of SUMOylated proteins from chromatin, leading to cell cycle arrest and apoptosis. Genome-scale CRISPR screens, in vitro ubiquitination assay, SUMO-interaction motif mapping, p97 recruitment assay, synthetic lethality double-knockout, cell cycle analysis Nature structural & molecular biology High 38649616
2024 TOPORS is recruited to SUMOylated DNMT1-DNA protein crosslinks (DPCs) and promotes their ubiquitin-dependent degradation; TOPORS knockout stabilizes SUMOylated DNMT1 following treatment with DNA hypomethylating agents (5-aza-dC); the TOPORS RING finger domain is responsible for this ubiquitination-mediated DPC resolution. CRISPR/Cas9 screens, proximity proteomics of DNMT1-DPC, TOPORS knockout/knockdown, SUMOylated DNMT1 immunoblot, RING domain mutant analysis The EMBO journal High 38760575
2024 TOPORS knockout predisposes leukemic blasts to impaired DNA damage response (DDR) and accumulation of SUMOylated DNMT1 when treated with HMAs; depletion of TOPORS synergizes with HMAs to reduce leukemic burden in xenograft models; combination does not impair healthy hematopoiesis. Genome-wide CRISPR-Cas9 screen, xenograft mouse model, SUMOylated DNMT1 immunoblot, DDR assays Nature communications High 39198401
2024 TOPORS knockout stabilizes DNMT1 by preventing its ubiquitination following HMA treatment, resulting in accumulation of unresolved SUMOylated DNMT1; the TOPORS RING finger domain mediates ubiquitination of SUMOylated DNMT1, promoting resolution of DNA-DNMT1 crosslinks. CRISPR-Cas9 knockout, DNMT1 stability assay, ubiquitination assay, RING finger domain analysis Nature communications High 39198387
2025 TOPORS is a SUMO1-selective STUbL that is recruited to PML only when sufficient SUMO1 conjugation occurs (not SUMO2/3 alone); arsenic-resistant PML mutant A216T fails to recruit TOPORS because arsenic does not trigger its SUMOylation; arsenic-resistant PML mutant L217F acquires SUMO2/3 but not SUMO1 conjugation sufficient to recruit TOPORS; thus TOPORS and RNF4 act in parallel on distinct SUMO chains to generate the polyubiquitin signal for p97 binding and PML degradation. PML-/- cell reconstitution with YFP-PML fusions (WT, A216T, L217F), arsenic treatment, SUMO-1 and SUMO2/3 conjugation assays, TOPORS and RNF4 recruitment assays The Journal of cell biology High 40239066
2025 TOPORS is identified as a substrate of the deubiquitinase USP7; USP7 inhibition leads to reduced TOPORS protein levels; TOPORS interacts with the BRCA1-A DNA damage repair complex, suggesting a USP7-TOPORS-BRCA1-A axis. Quantitative proteomics after USP7 inhibition, protein interaction network analysis (BRCA1-A complex co-identification) bioRxivpreprint Low bio_10.1101_2025.01.28.635372
2025 TOPORS regulates SUMO1 modification of TOP1 in macrophages exposed to ovalbumin-induced oxidative stress; knockdown of TOPORS reduces SUMO1-TOP1 levels and increases unrepaired DNA damage (γH2AX), indicating TOPORS-mediated TOP1 sumoylation contributes to DNA damage repair in this context. Immunoprecipitation of SUMO1-TOP1, siRNA knockdown of TOPORS, γH2AX immunoblot in OVA-stimulated macrophages Toxicology letters Medium 40532862
2001 LUN/TOPORS (RING finger protein) localizes to the nucleus and exhibits Zn2+-dependent DNA binding activity; the region from amino acids 51–374 is responsible for DNA binding; a palindromic binding consensus sequence (5'-TCCCAGCACTTTGGGA-3') was identified for LUN/TOPORS binding. Nuclear localization by immunofluorescence, DNA binding assay (Zn2+-dependence), deletion mapping, binding consensus identification The Journal of biological chemistry Medium 11278651

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. The Journal of biological chemistry 161 15247280
2005 Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS letters 136 16122737
2005 DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. International journal of oncology 133 15703819
2020 A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179. Cancer 132 32697352
2009 Plk1-mediated phosphorylation of Topors regulates p53 stability. The Journal of biological chemistry 81 19473992
2003 Forkhead transcription factor Foxf2 (LUN)-deficient mice exhibit abnormal development of secondary palate. Developmental biology 73 12812790
2007 Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. American journal of human genetics 68 17924349
2007 TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins. Journal of proteome research 51 17803295
2002 The topoisomerase I-binding RING protein, topors, is associated with promyelocytic leukemia nuclear bodies. Experimental cell research 50 12083797
2010 TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein. Human molecular genetics 48 21159800
2003 The DNA topoisomerase I binding protein topors as a novel cellular target for SUMO-1 modification: characterization of domains necessary for subcellular localization and sumolation. Experimental cell research 45 14516784
2005 topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage. Oncogene 44 15735665
2007 Chemotherapy in patients > or = 80 with advanced non-small cell lung cancer: combined results from SWOG 0027 and LUN 6. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 43 17545843
2007 Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1. The Journal of biological chemistry 39 18077445
2002 Wei Lun Visiting Professorial Lecture: Nitric oxide in the regulation of vascular function: an historical overview. Journal of cardiac surgery 39 12546077
2008 Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa. Molecular vision 37 18509552
2004 The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor. Oncogene 37 15107820
2007 The E3 ligase Topors induces the accumulation of polysumoylated forms of DNA topoisomerase I in vitro and in vivo. FEBS letters 36 17976381
2024 Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation. Nature structural & molecular biology 35 38649616
2022 TOPORS-mediated RAD51 SUMOylation facilitates homologous recombination repair. Nucleic acids research 31 35061896
2024 Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS. The EMBO journal 28 38760575
2010 Deficiency of the dual ubiquitin/SUMO ligase Topors results in genetic instability and an increased rate of malignancy in mice. BMC molecular biology 24 20429939
2001 Cloning and characterization of LUN, a novel ring finger protein that is highly expressed in lung and specifically binds to a palindromic sequence. The Journal of biological chemistry 24 11278651
1995 Paclitaxel plus carboplatin for advanced lung cancer: preliminary results of a Vanderbilt University phase II trial--LUN-46. Seminars in oncology 23 7644925
1998 Mouse forkhead (winged helix) gene LUN encodes a transactivator that acts in the lung. Genomics 21 9676429
2004 Expression of LUN gene that encodes a novel RING finger protein is correlated with development and progression of non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 18 15364129
2024 Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization. Nature communications 16 39198387
2009 Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene. Acta ophthalmologica 16 19183411
2004 Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. The Journal of biological chemistry 16 14871887
2020 TOPORS, a tumor suppressor protein, contributes to the maintenance of higher-order chromatin architecture. Biochimica et biophysica acta. Gene regulatory mechanisms 15 32113985
2005 A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p. Human genetics 13 16189705
2024 TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells. Nature communications 12 39198401
2016 TOPORS, a Dual E3 Ubiquitin and Sumo1 Ligase, Interacts with 26 S Protease Regulatory Subunit 4, Encoded by the PSMC1 Gene. PloS one 11 26872363
2008 Identification of phosphorylation sites of TOPORS and a role for serine 98 in the regulation of ubiquitin but not SUMO E3 ligase activity. Biochemistry 11 19053840
1996 Paclitaxel plus carboplatin in the treatment of patients with advanced lung cancer: a Vanderbilt University Cancer Center phase II trial (LUN-46). Seminars in oncology 8 9007120
2022 A Phase II Trial of Atezolizumab Plus Carboplatin Plus Pemetrexed Plus Bevacizumab in the Treatment of Patients with Stage IV Non-Squamous Non-Small Cell Lung Cancer: Big Ten Cancer Research Consortium (BTCRC)- LUN 17-139. Clinical lung cancer 7 36041949
2009 Plk1 phosphorylation of Topors is involved in its degradation. Molecular biology reports 7 19821153
2022 RING finger protein TOPORS modulates the expression of tumor suppressor SMAR1 in colorectal cancer via the TLR4-TRIF pathway. Molecular oncology 6 34689394
2012 TOPORS modulates H2AX discriminating genotoxic stresses. Journal of biochemical and molecular toxicology 6 22972498
2025 PML mutants from arsenic-resistant patients reveal SUMO1-TOPORS and SUMO2/3-RNF4 degradation pathways. The Journal of cell biology 5 40239066
2023 Comparative studies on the chemical composition and pharmacological effects of vinegar-processed antler glue modified from Lei Gong Pao Zhi Lun and traditional water-processed antler glue. Journal of ethnopharmacology 5 38065351
2022 Autosomal Dominant Retinitis Pigmentosa-Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867. Investigative ophthalmology & visual science 5 35579903
2012 Inhibition of PDGF-B induction and cell growth by syndecan-1 involves the ubiquitin and SUMO-1 ligase, Topors. PloS one 5 22912899
2017 A novel mutation in the dominantly inherited TOPORS gene supports haploinsufficiency as the mechanism of retinitis pigmentosa. Ophthalmic genetics 4 28453362
2009 Impact of the ASCO 2007 presentation of HOG Lun 01-24/USO-023 on the prescribing plans of American medical oncologists for patients with stage IIIB non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 4 19561551
2024 Autosomal Dominant Retinitis Pigmentosa Secondary to TOPORS Mutations: A Report of a Novel Mutation and Clinical Findings. Journal of clinical medicine 3 38592336
2024 Association of Immune-Related Adverse Events With Efficacy in Consolidation Nivolumab Plus Ipilimumab or Nivolumab Alone After Chemoradiation in Patients With Unresectable Stage III Nonsmall Cell Lung Cancer: An Exploratory Analysis From the Big 10 Cancer Research Consortium Study BTCRC LUN 16-081. Clinical lung cancer 3 39824659
2023 TOPORS as a novel causal gene for Joubert syndrome. American journal of medical genetics. Part A 3 37227088
2022 Mutations of TOPORS identified in families with retinitis pigmentosa. Ophthalmic genetics 3 35254173
2024 Phase Ib/II study of imprime PGG and pembrolizumab in patients with previously treated advanced non-small cell lung cancer (NSCLC): BTCRC LUN 15-017. Translational lung cancer research 2 39670007
2017 Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130. American journal of clinical oncology 2 25503432
2025 Modulation of SUMO1-TOP1 DNA damage repair by TOPORS following ovalbumin-induced oxidative stress in macrophages. Toxicology letters 1 40532862
2024 miR-198 targets TOPORS: implications for oral squamous cell carcinoma pathogenesis. Frontiers in oncology 1 39697236
2026 Study on the Role and Mechanism of TOPORS in Regulating Aortic Dissection by Mediating SUMOylation. Journal of cardiovascular development and disease 0 41892699
2025 Trigeminal Neuralgia in a 12-Month-Old Boy With Dandy-Walker Malformation and Homozygous Pathogenic TOPORS Variant. American journal of medical genetics. Part A 0 40358237
2019 Correction: The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor. Oncogene 0 31296957
2010 [Characteristics of acupuncture in Shanghan Lun (Treatise on Febrile Diseases)]. Zhongguo zhen jiu = Chinese acupuncture & moxibustion 0 20862948

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