Affinage

FZR1

Fizzy-related protein homolog · UniProt Q9UM11

Length
496 aa
Mass
55.2 kDa
Annotated
2026-06-09
54 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FZR1 (Cdh1/Fzr) is a substrate-recognition co-activator of the APC/C E3 ubiquitin ligase that drives ubiquitination and proteasomal degradation of cell-cycle regulators bearing RXXL destruction-box and KEN-box degrons (PMID:11179223, PMID:12198152). By recognizing these motifs it targets securin, Aurora A, and additional substrates, with KEN-box substrates degraded exclusively by APC/C(FZR1) while RXXL substrates can be shared with the CDC20-activated form (PMID:11179223, PMID:12198152, PMID:12023018). FZR1 acts predominantly during mitotic exit and G1/G0—mediating a cytoplasm-wide phase of cyclin B destruction distinct from the CDC20/Fzy-driven spindle-localized phase—and its loss in mammalian somatic cells shortens G1, prolongs S phase, and triggers DNA-damage responses rather than blocking mitotic exit (PMID:12082076, PMID:19861496). Its activity is gated by inactivating CDK4/6–cyclin D and ERK phosphorylation and reversed by phosphatases such as PRL-3, and FZR1 also catalyzes its own APC/C-dependent auto-degradation through internal destruction boxes (PMID:15029244, PMID:25562820, PMID:28174173, PMID:30498084). Centrosomal anchoring via direct binding to Spd2/CEP192 localizes APC/C(FZR1) activity toward centrosomal substrates including Aurora A and SPD-2/CEP192, coupling the ligase to centrosome duplication control (PMID:27558644, PMID:29030390, PMID:41278915). Beyond canonical cell-cycle control, FZR1 functions in meiotic prophase I quiescence and spindle-assembly timing in oocytes by repressing cyclin B1 (PMID:21270054, PMID:22918942), in post-mitotic neurons and epithelia through substrates such as Fasciclin2 and Nek2/Dishevelled (PMID:20890296, PMID:28041906), and in hematopoietic and cancer contexts by degrading RUNX1, BRAF, ANLN, and c-MYC (PMID:28174173, PMID:34635784, PMID:40346052, PMID:41713835). FZR1 additionally engages APC/C-independent roles, including suppression of BRAF dimerization, an H2B-ubiquitination/Myc transcriptional cascade driving endoreplication, and promotion of TRAF3/6 autoubiquitination to activate antiviral type I interferon signaling (PMID:28174173, PMID:32182338, PMID:41805567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2001 High

    Established that FZR1 confers substrate specificity on the APC/C through recognition of defined degron motifs, answering how the ligase selects its targets.

    Evidence In vitro APC/C ubiquitination of securin with destruction-box and KEN-box mutagenesis

    PMID:11179223

    Open questions at the time
    • Did not map FZR1 residues contacting the degrons
    • Limited to one substrate
  2. 2002 High

    Resolved how APC/C activator choice and degron type set the timing and order of substrate destruction, distinguishing FZR1 from CDC20 function.

    Evidence Swapped degron constructs with real-time degradation assays; Drosophila live imaging of cyclin B destruction phases; Aurora-A degradation assays

    PMID:12023018 PMID:12082076 PMID:12198152

    Open questions at the time
    • Aurora-A finding from single lab at Medium confidence
    • Structural basis of differential RXXL recognition not defined
  3. 2002 Medium

    Defined FZR1's organismal role as a G1 regulator acting redundantly with the Rb pathway, distinguishing it from a strict mitotic-exit function.

    Evidence C. elegans synthetic-lethal genetics with lin-35/Rb; Drosophila null-allele characterization

    PMID:11850412 PMID:12194827

    Open questions at the time
    • Molecular substrates underlying proliferation control not identified in these studies
    • Cross-species generality untested at the time
  4. 2004 High

    Showed FZR1 catalyzes its own destruction via APC/C, establishing an autoregulatory loop that limits its abundance.

    Evidence Xenopus interphase extract degradation assay with destruction-box mutagenesis and co-IP with APC/C

    PMID:15029244

    Open questions at the time
    • Physiological trigger for auto-degradation timing not defined
  5. 2009 High

    Demonstrated that in mammalian somatic cells FZR1 governs G1/S timing and genome stability rather than mitotic exit, redefining its mammalian role.

    Evidence RNAi in human cell lines and conditional knockout MEFs with cell-cycle and DNA-damage readouts

    PMID:19861496

    Open questions at the time
    • Specific substrates causing the S-phase/DNA-damage phenotype not pinned down
  6. 2009 Medium

    Placed FZR1 in the meiotic-arrest pathway downstream of CDC14B, linking phosphatase regulation to APC/C-mediated cyclin B1 control in oocytes.

    Evidence Overexpression and depletion epistasis in mouse oocytes

    PMID:19129509

    Open questions at the time
    • Direct dephosphorylation of FZR1 by CDC14B not shown
    • Single lab
  7. 2010 Medium

    Extended FZR1 function into post-mitotic biology, showing it patterns axonal adhesion molecules to guide glial migration.

    Evidence Drosophila fzr loss-of-function with imaging and fas2 epistasis

    PMID:20890296

    Open questions at the time
    • Whether Fas2 distribution is controlled via direct APC/C substrate turnover unclear
    • Single organism
  8. 2011 High

    Established that APC/C(FZR1) maintains meiotic prophase I quiescence by repressing cyclin B1 levels in vivo.

    Evidence Oocyte-specific conditional knockout with cyclin B1 knockdown rescue

    PMID:21270054

    Open questions at the time
    • Other meiotic substrates not characterized
  9. 2012 High

    Showed FZR1 controls meiotic spindle-assembly timing and embryonic syngamy, linking its activity to chromosome segregation fidelity.

    Evidence Oocyte-specific and maternal-zygotic Fzr1 knockouts with live imaging and SAC markers

    PMID:22918942 PMID:23097041

    Open questions at the time
    • Mechanism connecting FZR1 to spindle assembly rate undefined
    • Syngamy study single lab at Medium confidence
  10. 2015 High

    Identified inactivating CDK4/6–cyclin D phosphorylation of FZR1, linking it to CDK4/6-inhibitor response and revealing a cooperative axis with Rb.

    Evidence C. elegans genetic screen, phospho-site mapping, and RNAi/CDK4-6 inhibitor assays in human breast cancer cells

    PMID:25562820

    Open questions at the time
    • Full repertoire of CDK-regulated FZR1 sites in humans not completely mapped
  11. 2016 High

    Defined how FZR1 is spatially targeted, showing direct Spd2 binding localizes APC/C(FZR1) to centrosomes for efficient Aurora A degradation.

    Evidence Co-IP, binding-defective Spd2 mutants, and centrosomal APC/C activity assays in Drosophila

    PMID:27558644

    Open questions at the time
    • Conservation of Spd2-mediated anchoring in mammals not addressed here
  12. 2016 Medium

    Expanded the FZR1 substrate set in disease, identifying TOPIIα degradation and an FZR1 dependency in multiple myeloma.

    Evidence siRNA, substrate accumulation Westerns, and proTAME treatment in myeloma cells

    PMID:27655696

    Open questions at the time
    • Direct ubiquitination of TOPIIα by FZR1 not reconstituted
    • Single lab
  13. 2016 Medium

    Revealed a post-mitotic developmental role in planar cell polarity through the FZR1–Nek2–Dishevelled axis.

    Evidence Drosophila genetics, epistasis, and substrate degradation assays

    PMID:28041906

    Open questions at the time
    • Mammalian conservation untested
    • Single lab
  14. 2017 High

    Uncovered dual APC/C-dependent and APC/C-independent suppression of BRAF by FZR1 and its inactivation by ERK and CDK4, connecting FZR1 to oncogenic MAPK signaling.

    Evidence Ubiquitination assays, dimerization co-IP, phospho-site mapping, and Fzr1/Pten mouse model with inhibitor treatments

    PMID:28174173

    Open questions at the time
    • Relative contribution of degradation versus dimerization disruption in vivo not quantified
  15. 2017 Medium

    Showed FZR1 controls centrosome duplication by degrading SAS-5 via KEN-box recognition, linking the ligase to centriole number control.

    Evidence C. elegans fzr-1 genetics with SAS-5 KEN-box mutagenesis and centrosome assays

    PMID:29030390

    Open questions at the time
    • Mammalian SAS-5 orthologs not tested
    • Single lab
  16. 2018 Medium

    Identified PRL-3 as an activating phosphatase that dephosphorylates FZR1 to drive AURKA degradation, complementing the kinase-based inactivation model.

    Evidence Co-IP, ubiquitination assay, and phosphatase-dead PRL-3 mutant

    PMID:30498084

    Open questions at the time
    • Specific FZR1 residues dephosphorylated by PRL-3 not mapped
    • Single lab
  17. 2020 High

    Established that CDK phosphorylation of FZR1 is required in vivo for the meiotic II transition in male germ cells, defining a germline-specific regulatory requirement.

    Evidence Non-phosphorylatable Fzr1 knock-in mice with testis histology and substrate Westerns

    PMID:32572094

    Open questions at the time
    • Substrates whose mistimed turnover causes the meiosis II failure not fully defined
  18. 2020 Medium

    Revealed an APC/C-independent transcriptional role in which FZR1 promotes H2B ubiquitination at the Myc promoter to drive endoreplication.

    Evidence Co-IP, ChIP, and reporter assays in Drosophila with mammalian validation

    PMID:32182338

    Open questions at the time
    • Mechanism by which FZR1 stimulates H2B ubiquitination not biochemically reconstituted
    • Single lab
  19. 2021 Medium

    Connected FZR1 to hematopoietic stem cell biology and aplastic anemia through site-specific RUNX1 ubiquitination.

    Evidence Ubiquitination assay with K125 mutant, Fzr1+/- mice, and RUNX1 knockdown rescue in HSCs

    PMID:34635784

    Open questions at the time
    • Whether RUNX1 turnover is APC/C-dependent not isolated
    • Single lab
  20. 2021 Medium

    Defined a direct FZR1–pRB interaction via an LxCxD motif separable from core APC/C binding, controlling SKP2/PLK1 and CDK-inhibitor levels and S-phase entry.

    Evidence Point mutagenesis, in vitro binding, HPV E7 competition, and cell-cycle analysis

    PMID:33971196

    Open questions at the time
    • Functional significance of pRB binding in normal tissue not established
    • Single lab
  21. 2022 Medium

    Re-mapped the Aurora A degron, showing the N-terminal A-box rather than the C-terminal D-box confers FZR1-dependent degradation.

    Evidence In cellulo degradation assays with AURKA deletion and mutation constructs

    PMID:36450448

    Open questions at the time
    • Structural basis of A-box recognition by FZR1 not solved
    • Single lab
  22. 2023 Medium

    Showed FZR1 abundance is set translationally via m6A-dependent GEMIN5/eIF3 recruitment, coupling FZR1 to quiescence and chemoresistance in pancreatic cancer.

    Evidence m6A profiling, GEMIN5–FZR1 mRNA co-IP, eIF3 co-IP, and FZR1 knockdown

    PMID:37326469

    Open questions at the time
    • Whether translational upregulation broadly governs FZR1 levels beyond this context unclear
    • Single lab
  23. 2025 Medium

    Expanded oncogenic substrate recognition, showing FZR1 degrades ANLN and c-MYC and that competing factors stabilize these substrates to drive cancer progression.

    Evidence Ubiquitination assays with substrate-site mutagenesis, competitive co-IP, and functional cancer assays

    PMID:40346052 PMID:41713835

    Open questions at the time
    • APC/C dependence of ANLN and c-MYC degradation not isolated
    • Each finding single lab
  24. 2025 Medium

    Demonstrated germline stem cell roles, with APC/C(FZR-1) degrading chromatin regulators MES-3/MES-4 under Notch control during oocyte differentiation.

    Evidence C. elegans fzr-1 and APC/C genetics with substrate quantification and Notch epistasis

    PMID:40446035

    Open questions at the time
    • Direct degron recognition of MES proteins not mapped
    • Single lab
  25. 2025 Medium

    Established stabilizing regulation of FZR1 by USP8 deubiquitination and Hsp70-assisted folding required for endoreplication.

    Evidence Co-IP, deubiquitination assay, and genetic depletion in Drosophila and Bombyx

    PMID:40106570

    Open questions at the time
    • Mammalian relevance of USP8/Hsp70 control untested
    • Single lab
  26. 2025 Medium

    Revealed an APC/C-independent antiviral role in which FZR1 promotes TRAF3/6 autoubiquitination and MAVS aggregation to activate type I interferon signaling.

    Evidence Co-IP, autoubiquitination and MAVS aggregation assays, FZR1 knockout cells and mice, and inhibitor treatment

    PMID:41805567

    Open questions at the time
    • Direct ligase mechanism on TRAF3/6 versus a scaffolding role not fully separated
    • Novel function from single lab
  27. 2025 Medium

    Provided evidence that SPD-2/CEP192 is an FZR1 substrate with multiple D-boxes differentially controlling centrosomal localization and duplication.

    Evidence In vivo co-IP and systematic D-box mutagenesis with centrosome duplication rescue (preprint)

    PMID:41278915

    Open questions at the time
    • Preprint, not peer reviewed
    • Mammalian CEP192 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FZR1 mechanistically partitions between its canonical APC/C co-activator function and its growing set of APC/C-independent activities, and the structural basis for its diverse degron and protein-interaction recognition, remains unresolved.
  • No structural model of FZR1 bound to its various degrons
  • Switch governing APC/C-dependent versus -independent modes not defined
  • Mammalian conservation of several invertebrate findings untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005815 microtubule organizing center 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1474165 Reproduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 1
Partners
GEMIN5NEK2PRL-3RB1SPD2/CEP192TRAF3TRAF6USP8
Complex memberships
APC/C

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 FZR1 (Fzr/Cdh1) activates the APC/C to ubiquitinate and degrade human securin/PTTG in vitro. Securin degradation is mediated by both an RXXL destruction box and a KEN box; mutation of both sequences together is required to prevent ubiquitination and degradation. In vitro APC/C ubiquitination assay; destruction box/KEN box mutagenesis; cell-based expression of non-degradable securin mutant The EMBO journal High 11179223
2002 Drosophila Fzr/Cdh1 binds microtubules in vitro and associates with spindles in vivo, concentrating at centrosomes throughout the cell cycle. Fzr/Cdh1 is responsible for the second, cytoplasm-wide phase of cyclin B destruction during mitotic exit, distinct from the spindle-localized destruction driven by Fzy/Cdc20. Microtubule-binding assay in vitro; in vivo live imaging and immunofluorescence; destruction-box mutant cyclin B (CBTPM-GFP) degradation assay in syncytial vs. cellularized embryos The Journal of cell biology High 12082076
2002 APC/C(FZR1)-dependent degradation timing is determined by the specificity of destruction box (RXXL) and KEN box motifs. KEN-box substrates are degraded exclusively by APC/C(Fzr); RXXL substrates can be degraded by both APC/C(Fzy) and APC/C(Fzr), but APC/C(Fzy)-specific RXXL degradation is highly dependent on the location of the RXXL within the substrate. APC/C(Fzr) is activated in early G1. Swapped destruction box mutant constructs; real-time fluorescence-based degradation assay; in vitro APC/C ubiquitination assay The EMBO journal High 12198152
2002 Human Aurora-A kinase is targeted for degradation by APC/C(hCdh1/FZR1) in vivo, dependent on its destruction box, KEN box motifs, and its kinase activity. hCdc20 does not mediate Aurora-A degradation. Co-expression and immunoprecipitation; in vivo degradation assay with destruction box and KEN box mutants; kinase-dead mutant analysis FEBS letters Medium 12023018
2002 C. elegans fzr-1 (Cdh1 homolog) functions redundantly with lin-35/Rb to control cell proliferation. Genetic epistasis places fzr-1 in a pathway regulating cyclin levels and cell cycle progression; simultaneous loss of both fzr-1 and lin-35 produces severe proliferation defects not seen with either single mutant. Synthetic-lethal genetic screen; double-mutant epistasis analysis in C. elegans Genes & development Medium 11850412
2002 Drosophila Fzr (encoded by fzr/rap) is essential during G1 but not for mitotic exit including cyclin B degradation. FZR accumulates predominantly in the cytoplasm in Drosophila cells. Loss of fzr causes lethality corresponding to the rap locus. Genetic null allele characterization; fzr2 expression analysis; cell fractionation/localization; cyclin B degradation assay in fzr mutants Current biology : CB Medium 12194827
2004 Mammalian Cdh1/FZR1 mediates its own degradation by activating the APC/C to ubiquitinate itself via two RXXL-type destruction boxes. In G1/G0, Cdh1 is nearly entirely APC/C-associated and present at lower levels. Addition of Cdh1 to Xenopus interphase extracts activates APC/C to degrade Cdh1 itself. In vitro Xenopus interphase extract degradation assay; destruction box mutagenesis; co-immunoprecipitation of Cdh1 with APC/C; Western blot cell cycle analysis The EMBO journal High 15029244
2009 Loss of FZR1 in human cell lines (RNAi) and mouse embryonic fibroblasts (conditional knockout) shortens G1 phase and prolongs S phase, induces DNA-damage responses, and impairs proliferation independently of p53 status. FZR1 is not required for mitotic exit in mammalian somatic cells. RNAi knockdown in human cell lines; conditional gene targeting in MEFs; cell cycle analysis; DNA damage response markers Journal of cell science High 19861496
2009 CDC14B phosphatase prevents meiotic resumption in mouse oocytes through FZR1 (Cdh1). Depletion of FZR1 partially restores normal meiotic timing in oocytes with excess CDC14B, placing FZR1 downstream of CDC14B in controlling APC/C-mediated cyclin B1 proteolysis and prophase I arrest. mRNA injection for overexpression; morpholino/siRNA depletion of FZR1 and CDC14B in mouse oocytes; epistasis analysis; localization studies Biology of reproduction Medium 19129509
2010 APC/C(Fzr/Cdh1) controls peripheral glial migration in post-mitotic Drosophila neurons by regulating the axonal distribution of the cell adhesion molecule Fasciclin2 (Fas2). Fzr/Cdh1 establishes a graded axonal Fas2 distribution, and axonal Fas2 interacts homophilically with a glial isoform to guide glial migration. Genetic loss-of-function (fzr mutants); immunofluorescence; in vivo imaging of glial migration; epistasis with fas2 alleles Nature neuroscience Medium 20890296
2011 APC/C(FZR1) activity in mouse oocytes is required to repress cyclin B1 levels during prophase I arrest, maintaining meiotic quiescence. In oocyte-specific Fzr1 knockout mice, cyclin B1 levels are ~5-fold elevated, prophase I/GV arrest is compromised, and cyclin B1 knockdown in Fzr1-null oocytes partially rescues the timing of meiotic resumption. Oocyte-specific conditional knockout; Western blot; cyclin B1 knockdown rescue experiment; in vitro oocyte maturation assay Development (Cambridge, England) High 21270054
2012 FZR1 controls the timing of bipolar meiotic spindle assembly in mouse oocytes, thereby regulating when the spindle assembly checkpoint (SAC) is satisfied and APC/C(CDC20) becomes active. Loss of FZR1 accelerates spindle assembly, leading to premature bivalent attachment, poor chromosome congression, and 25% nondisjunction. FZR1 loss does not abrogate SAC functionality. Oocyte-specific Fzr1 conditional knockout; live imaging; SAC marker (MAD2) localization; spindle assembly timing assay Molecular biology of the cell High 22918942
2012 Maternal and zygotic FZR1 is required for syngamy (establishment of a single spindle from two pronuclei) and maintenance of genomic integrity during the first mitotic divisions of mouse embryos. Absence of both maternal and paternal FZR1 leads to formation of two independent spindles after pronuclear fusion, binucleate 2-cell embryos, and embryonic arrest. Oocyte-specific knockout (maternal FZR1 depleted) crossed to zygotic null; γ-H2AX foci imaging; live imaging of spindle formation Journal of cell science Medium 23097041
2015 FZR1 is a substrate of CDK4/6-cyclin D kinase. CDK-4/CYD-1 phosphorylates specific residues in the FZR-1 amino terminus (C. elegans), resembling inactivating phosphorylations of human FZR1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically bypasses cell division arrest induced by the CDK4/6-specific inhibitor PD-0332991. Unbiased genetic screen in C. elegans; phosphorylation site mapping; RNAi double knockdown in human breast cancer cells; CDK4/6 inhibitor rescue assay Nature communications High 25562820
2016 Drosophila Fzr/Cdh1 localizes to centrioles during interphase via direct interaction with the centrosome component Spd2. This centrosomal localization is essential for optimal APC/C activation toward its centrosomal substrate Aurora A. Spd2 is itself a novel APC/C(Fzr) substrate. Co-immunoprecipitation; Spd2 mutants unable to bind Fzr; in vivo localization (immunofluorescence); APC/C activity assays toward Aurora A substrate Nature communications High 27558644
2016 APC/C(FZR1) ubiquitinates Topoisomerase IIα (TOPIIα) for degradation. Knockdown of FZR1 in multiple myeloma cells reduces viability and induces growth arrest, with accumulation of TOPIIα as a substrate readout. siRNA knockdown; Western blot for substrate accumulation (TOPIIα); cell viability assay; APC/C inhibitor (proTAME) Oncotarget Medium 27655696
2016 APC/C(Fzr/Cdh1) negatively regulates Nek2 kinase (a direct substrate targeted for ubiquitination and degradation), which in turn negatively regulates the PCP factor Dishevelled. Loss of APC/C function in Drosophila leads to reduced Dishevelled levels through Nek2 accumulation, establishing a post-mitotic role for APC/C(Fzr) in epithelial planar cell polarity. Genetic loss-of-function; epistasis analysis; in vivo substrate degradation assay; immunofluorescence Developmental cell Medium 28041906
2017 FZR1 inhibits BRAF through two distinct mechanisms: (1) APC/C(FZR1) ubiquitinates BRAF for proteasomal degradation in primary cells; (2) APC/C-free FZR1 suppresses BRAF by disrupting BRAF dimerization. ERK and CYCLIN D1/CDK4 phosphorylate FZR1 to inhibit APC/C(FZR1) activity. CDK4 and/or BRAF/MEK inhibitors restore APC/C(FZR1) activity. Co-immunoprecipitation; ubiquitination assays; FZR1 phosphorylation site identification; in vivo mouse model (Fzr1 ablation with Pten loss); pharmacological inhibitor treatments Cancer discovery High 28174173
2018 PRL-3 phosphatase dephosphorylates FZR1, which activates the APC/C(FZR1) complex, leading to enhanced AURKA ubiquitination and degradation. PRL-3 physically interacts with both AURKA and FZR1. Co-immunoprecipitation; ubiquitination assay; phosphatase-dead PRL-3 mutant; Western blot for AURKA levels upon PRL-3/FZR1 manipulation Cancer research Medium 30498084
2020 CDK-mediated phosphorylation of FZR1 is required for entry into meiosis II in mouse male germ cells in vivo. Non-phosphorylatable FZR1 knock-in mice show normal somatic cell cycles but male infertility due to failure to enter meiosis II and form spermatids, associated with dysregulated APC/C activity. Non-phosphorylatable knock-in mouse model (CDK-site substitution); testis histology; germ cell meiosis progression analysis; Western blot for FZR1 substrates Scientific reports High 32572094
2020 Fzr/Cdh1 interacts with chromatin-associated histone H2B to enhance H2B ubiquitination at the Myc promoter, promoting Myc transcription, which in turn drives MCM6 expression to promote DNA replication during endoreplication. This non-APC/C transcriptional cascade is conserved between Drosophila and mammalian cells. Co-immunoprecipitation; ChIP; promoter reporter assays; genetic knockdown of fzr; conservation validated in mammalian cells Nucleic acids research Medium 32182338
2021 FZR1 ubiquitinates RUNX1 at lysine 125, targeting it for proteasomal degradation. FZR1 insufficiency leads to RUNX1 accumulation, which disrupts HSC quiescence and self-renewal in aplastic anemia. Ubiquitination assay with K125 mutation; Fzr1 heterozygous knockout mouse models; RUNX1 knockdown rescue in Fzr1+/- HSCs; in vivo repopulation assay Leukemia Medium 34635784
2021 FZR1 interacts with pRB via an LxCxD motif; the cysteine residue in this motif is critical for direct binding to pRB's LxCxE-binding pocket. Mutation of this cysteine disrupts pRB interaction but not FZR1 association with core APC/C. FZR1 LxCxD mutant cells show accumulation of SKP2 and PLK1, downregulation of p27Kip1 and p21Cip1, and premature S-phase entry. Point mutagenesis; in vitro binding assay; competition with HPV E7; co-immunoprecipitation; cell cycle analysis Experimental cell research Medium 33971196
2022 The reported C-terminal D-box of Aurora A (AURKA) does not function as a degron for APC/C(FZR1)-dependent degradation; instead, it mediates essential structural features of the protein. The N-terminal A-box (containing the QRVL motif, a phospho-regulated D-box) in the intrinsically disordered region of AURKA is sufficient to confer FZR1-dependent mitotic degradation. In cellulo degradation assays with AURKA deletion/mutation constructs; in silico D-box prediction; cell-based FZR1-dependent degradation assay with N-terminal fragment Life science alliance Medium 36450448
2017 APC/C(FZR-1) in C. elegans regulates centrosome duplication by controlling SAS-5 protein levels. FZR-1 directly recognizes the KEN-box motif of SAS-5 to promote its degradation. FZR-1 associates with centrosomes and is enriched at nuclei during mitotic cell division in early embryos. fzr-1 loss-of-function genetics; immunofluorescence for FZR-1 localization; centrosome duplication assay; KEN-box mutant analysis of SAS-5 G3 (Bethesda, Md.) Medium 29030390
2025 In C. elegans, APC/C(FZR-1) facilitates the degradation of chromatin regulators MES-4 and MES-3 when germline stem cells transition toward oocyte differentiation. Notch signaling from the distal tip cell restricts APC/C(FZR-1) activity to allow MES-3 and MES-4 accumulation in GSCs and maintain stemness. Genetic loss-of-function of fzr-1 and APC/C subunits; protein level measurements by immunofluorescence; epistasis with Notch pathway mutants Science advances Medium 40446035
2025 SPD-2 (homolog of human CEP192) is a substrate of APC/C(FZR-1) in C. elegans embryos. SPD-2 physically associates with FZR-1 in vivo. Three distinct D-box motifs in SPD-2 contribute differentially to degradation and centrosomal localization: D-box3 mutation stabilizes centrosomal SPD-2 and restores centrosome duplication in zyg-1 mutants, while D-box1 mutation reduces centrosomal SPD-2 and worsens duplication defects. Co-immunoprecipitation (FZR-1 and SPD-2 in vivo); D-box site mutagenesis; centrosome duplication rescue assay; immunofluorescence bioRxivpreprint Medium 41278915
2025 FZR1/Cdh1 promotes TRAF3 and TRAF6 autoubiquitination independently of the APC/C, attenuates MAVS binding to PFKFB3, promotes MAVS aggregation, and thereby activates IRF3 and NF-κB to drive type I interferon and proinflammatory cytokine production during RNA virus infection. This antiviral function is enhanced by m6A-mediated increase in FZR1 translation upon VSV infection. Co-immunoprecipitation; ubiquitination assay (TRAF3/6 autoubiquitination); MAVS aggregation assay; FZR1 knockout cells and mice; pharmacological FZR1 inhibition Proceedings of the National Academy of Sciences of the United States of America Medium 41805567
2025 USP8 deubiquitinase interacts with FZR1 (Fzr) and deubiquitinates it to promote its stabilization, which is required for endoreplication in Drosophila salivary gland and Bombyx silk gland. Hsp70 mediates proper folding of Fzr and increases the Fzr-USP8 interaction, thereby enhancing Fzr deubiquitination. Co-immunoprecipitation; deubiquitination assay; genetic depletion of USP8 and Hsp70; endoreplication assay Science advances Medium 40106570
2023 GEMIN5, an m6A reader protein, binds m6A-modified FZR1 mRNA and recruits the eIF3 translation initiation complex, accelerating FZR1 protein translation. Elevated FZR1 protein maintains G0-G1 quiescence and suppresses gemcitabine sensitivity in pancreatic cancer cells. m6A profiling; GEMIN5-FZR1 mRNA Co-IP; eIF3 complex co-immunoprecipitation; FZR1 knockdown; cell cycle analysis Cancer research Medium 37326469
2025 FZR1 ubiquitinates ANLN (Anillin) for degradation. CCNE1 (Cyclin E1) competes with FZR1-mediated ANLN ubiquitination by binding ANLN and stabilizing it, promoting TNBC stemness and progression. Mutation of the ANLN ubiquitination site abolishes CCNE1's regulatory effect. Co-immunoprecipitation; ubiquitination assay; ANLN ubiquitination site mutagenesis; CCNE1 knockdown/overexpression; in vitro and in vivo functional assays Cell death discovery Medium 40346052
2026 FZR1 ubiquitinates c-MYC for proteasomal degradation. DSN1 competes with c-MYC for FZR1 binding, thereby attenuating c-MYC ubiquitination and stabilizing c-MYC to promote colorectal cancer metastasis. Co-immunoprecipitation; ubiquitination assay; cycloheximide chase; proteasome inhibition; rescue experiment with c-MYC overexpression Experimental cell research Medium 41713835

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis. The EMBO journal 197 11179223
2002 The roles of Fzy/Cdc20 and Fzr/Cdh1 in regulating the destruction of cyclin B in space and time. The Journal of cell biology 139 12082076
2002 fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen. Genes & development 128 11850412
2004 Mammalian Cdh1/Fzr mediates its own degradation. The EMBO journal 100 15029244
2002 Degradation of human Aurora-A protein kinase is mediated by hCdh1. FEBS letters 92 12023018
2009 Loss of the mammalian APC/C activator FZR1 shortens G1 and lengthens S phase but has little effect on exit from mitosis. Journal of cell science 81 19861496
2002 Timing of APC/C substrate degradation is determined by fzy/fzr specificity of destruction boxes. The EMBO journal 74 12198152
2017 The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function. Cancer discovery 63 28174173
2015 Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells. Nature communications 62 25562820
2009 CDC14B acts through FZR1 (CDH1) to prevent meiotic maturation of mouse oocytes. Biology of reproduction 60 19129509
2011 The APC/C activator FZR1 coordinates the timing of meiotic resumption during prophase I arrest in mammalian oocytes. Development (Cambridge, England) 55 21270054
2010 APC/C(Fzr/Cdh1)-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS. Nature neuroscience 53 20890296
2002 Completion of mitosis requires neither fzr/rap nor fzr2, a male germline-specific Drosophila Cdh1 homolog. Current biology : CB 52 12194827
2000 Overexpression of murine fizzy-related (fzr) increases natural killer cell-mediated cell death and suppresses tumor growth. Blood 39 10891459
2001 A novel Cdc20-related WD-repeat protein, Fzr1, is required for spore formation in Schizosaccharomyces pombe. Molecular genetics and genomics : MGG 37 11405625
2018 PRL-3 Promotes Ubiquitination and Degradation of AURKA and Colorectal Cancer Progression via Dephosphorylation of FZR1. Cancer research 35 30498084
2016 Targeting of Fzr/Cdh1 for timely activation of the APC/C at the centrosome during mitotic exit. Nature communications 34 27558644
2012 APC(FZR1) prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing. Molecular biology of the cell 32 22918942
2014 The APC/C activator FZR1 is essential for meiotic prophase I in mice. Development (Cambridge, England) 26 24553289
2008 Functions of FZR1 and CDC20, activators of the anaphase-promoting complex, during meiotic maturation of swine oocytes. Biology of reproduction 25 18753608
2016 Identification of the APC/C co-factor FZR1 as a novel therapeutic target for multiple myeloma. Oncotarget 24 27655696
2006 Terminal mitoses require negative regulation of Fzr/Cdh1 by Cyclin A, preventing premature degradation of mitotic cyclins and String/Cdc25. Development (Cambridge, England) 24 16854973
2011 Mes1 controls the meiosis I to meiosis II transition by distinctly regulating the anaphase-promoting complex/cyclosome coactivators Fzr1/Mfr1 and Slp1 in fission yeast. Molecular biology of the cell 23 21389117
2005 rap gene encodes Fizzy-related protein (Fzr) and regulates cell proliferation and pattern formation in the developing Drosophila eye-antennal disc. Developmental biology 23 16098963
2023 Fzr regulates silk gland growth by promoting endoreplication and protein synthesis in the silkworm. PLoS genetics 21 36652497
2020 FZR1 as a novel biomarker for breast cancer neoadjuvant chemotherapy prediction. Cell death & disease 21 32978372
2016 APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled. Developmental cell 20 28041906
2020 A novel transcriptional cascade is involved in Fzr-mediated endoreplication. Nucleic acids research 19 32182338
2017 FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia. Blood 18 28143883
2013 Cuf2 boosts the transcription of APC/C activator Fzr1 to terminate the meiotic division cycle. EMBO reports 16 23628763
2023 N 6-methyladenosine Modification of FZR1 mRNA Promotes Gemcitabine Resistance in Pancreatic Cancer. Cancer research 15 37326469
2008 Regulation of glia number in Drosophila by Rap/Fzr, an activator of the anaphase-promoting complex, and Loco, an RGS protein. Genetics 15 18430931
2022 De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies. Brain : a journal of neurology 14 34788397
2012 The APC activator fizzy-related-1 (FZR1) is needed for preimplantation mouse embryo development. Journal of cell science 10 23097041
2017 APC/CFZR-1 Controls SAS-5 Levels To Regulate Centrosome Duplication in Caenorhabditis elegans. G3 (Bethesda, Md.) 9 29030390
2020 Phosphorylation of the Anaphase Promoting Complex activator FZR1/CDH1 is required for Meiosis II entry in mouse male germ cell. Scientific reports 8 32572094
2007 A genetic modifier screen identifies multiple genes that interact with Drosophila Rap/Fzr and suggests novel cellular roles. Journal of neurogenetics 8 17849284
2017 Fission yeast APC/C activators Slp1 and Fzr1 sequentially trigger two consecutive nuclear divisions during meiosis. FEBS letters 7 28245054
2023 Association of Hsp90 with p53 and Fizzy related homolog (Fzr) synchronizing Anaphase Promoting Complex (APC/C): An unexplored ally towards oncogenic pathway. Biochimica et biophysica acta. Reviews on cancer 5 36972769
2022 Revisiting degron motifs in human AURKA required for its targeting by APC/CFZR1. Life science alliance 5 36450448
2021 Insufficiency of FZR1 disturbs HSC quiescence by inhibiting ubiquitin-dependent degradation of RUNX1 in aplastic anemia. Leukemia 5 34635784
2020 Fzr/Cdh1 Promotes the Differentiation of Neural Stem Cell Lineages in Drosophila. Frontiers in cell and developmental biology 5 32117986
2025 USP8 and Hsp70 regulate endoreplication by synergistically promoting Fzr deubiquitination and stabilization. Science advances 4 40106570
2025 CCNE1 stabilizes ANLN by counteracting FZR1-mediated the ubiquitination modification to promotes triple negative breast cancer cell stemness and progression. Cell death discovery 4 40346052
2018 APC/CFzr regulates cardiac and myoblast cell numbers, and plays a crucial role during myoblast fusion. Journal of cell science 4 29898917
2013 Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 4 23933137
2021 LxCxD motif of the APC/C coactivator subunit FZR1 is critical for interaction with the retinoblastoma protein. Experimental cell research 3 33971196
2024 Knockdown of Fzr inhibited the growth of Nilaparvata lugens by blocking endocycle. Pest management science 2 39229824
2026 Fzr knockdown disrupts cell cycle transition in ovarian follicle cells of Nilaparvata lugens. Insect science 0 41553232
2026 DSN1 promotes colorectal cancer metastasis by Inhibiting FZR1-Mediated ubiquitination of c-MYC. Experimental cell research 0 41713835
2026 N6-methyladenosine modification of FZR1 mRNA positively regulates antiviral innate immunity by targeting the MAVS-TRAF3/6 axis. Proceedings of the National Academy of Sciences of the United States of America 0 41805567
2025 Notch controls APC/CFZR-1 to enable accumulation of chromatin regulators in germline stem cells from Caenorhabditis elegans. Science advances 0 40446035
2025 Distinct D-box Motifs in SPD-2 Mediate APC/CFZR-1-Dependent Degradation and Centrosomal Localization in Caenorhabditis elegans Embryos. bioRxiv : the preprint server for biology 0 41278915
2017 Anaphase-Promoting Complex Adaptor FZR1/CDH1 Blocks BRAF Signaling Both by Targeting BRAF for Proteolytic Degradation and by Disrupting BRAF Dimerization. Cancer discovery 0 28373167

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