FZR1

Summary

FZR1 (fizzy and cell division cycle 20 related 1, HGNC:24824) is a protein-coding gene on chromosome 19p13.3, encoding Fizzy-related protein homolog (Q9UM11). Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. It is a selective cancer dependency (DepMap: 13.2% of cell lines).

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in anaphase-promoting complex-dependent catabolic process; mitotic G2 DNA damage checkpoint signaling; and positive regulation of ubiquitin protein ligase activity. Located in nuclear membrane and nucleoplasm. Implicated in developmental and epileptic encephalopathy 109.

Source: NCBI Gene 51343 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy 109 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 82 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 73
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 13.2% of screened cell lines
• MANE Select transcript: NM_016263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24824
Approved symbol	FZR1
Name	fizzy and cell division cycle 20 related 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HCDH1, CDH1, HCDH, FZR, FZR2, KIAA1242, CDC20C
Ensembl gene	ENSG00000105325
Ensembl biotype	protein_coding
OMIM	603619
Entrez	51343

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000313639, ENST00000395095, ENST00000441788, ENST00000586212, ENST00000588084, ENST00000588327, ENST00000591290, ENST00000592214, ENST00000652521, ENST00000876598, ENST00000876599, ENST00000876600, ENST00000876601, ENST00000876602, ENST00000876603, ENST00000876604, ENST00000876605, ENST00000928282, ENST00000928283, ENST00000928284, ENST00000928285, ENST00000928286, ENST00000951911, ENST00000951912, ENST00000951913

RefSeq mRNA: 3 — MANE Select: NM_016263 NM_001136197, NM_001136198, NM_016263

CCDS: CCDS12109, CCDS45916, CCDS45917

Canonical transcript exons

ENST00000441788 — 14 exons

Exon	Start	End
ENSE00000664430	3532417	3532650
ENSE00000664431	3531911	3532095
ENSE00000664432	3531714	3531816
ENSE00000664437	3526120	3526183
ENSE00001691059	3506311	3506474
ENSE00001735485	3534795	3538334
ENSE00003461236	3526259	3526386
ENSE00003529318	3530792	3530857
ENSE00003537741	3525868	3525993
ENSE00003551656	3534421	3534513
ENSE00003588826	3522956	3523058
ENSE00003623927	3526980	3527062
ENSE00003666085	3533294	3533398
ENSE00003675566	3527631	3527814

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 95.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1060 / max 416.4947, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173202	19.3755	1808
173203	0.7305	368

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.13	gold quality
left testis	UBERON:0004533	95.00	gold quality
right testis	UBERON:0004534	94.73	gold quality
sural nerve	UBERON:0015488	92.76	gold quality
adenohypophysis	UBERON:0002196	92.57	gold quality
testis	UBERON:0000473	92.50	gold quality
ganglionic eminence	UBERON:0004023	92.19	gold quality
cortical plate	UBERON:0005343	92.08	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.82	gold quality
skin of leg	UBERON:0001511	91.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.55	gold quality
tendon of biceps brachii	UBERON:0008188	91.51	gold quality
lower esophagus mucosa	UBERON:0035834	91.48	gold quality
pituitary gland	UBERON:0000007	91.47	gold quality
stromal cell of endometrium	CL:0002255	91.20	gold quality
cerebellar hemisphere	UBERON:0002245	91.01	gold quality
skin of abdomen	UBERON:0001416	90.93	gold quality
cerebellar cortex	UBERON:0002129	90.93	gold quality
buccal mucosa cell	CL:0002336	90.59	silver quality
ectocervix	UBERON:0012249	90.49	gold quality
right adrenal gland cortex	UBERON:0035827	90.20	gold quality
right adrenal gland	UBERON:0001233	90.02	gold quality
left adrenal gland cortex	UBERON:0035825	90.02	gold quality
endocervix	UBERON:0000458	89.96	gold quality
right uterine tube	UBERON:0001302	89.83	gold quality
esophagus mucosa	UBERON:0002469	89.80	gold quality
right lobe of thyroid gland	UBERON:0001119	89.79	gold quality
prefrontal cortex	UBERON:0000451	89.77	gold quality
left lobe of thyroid gland	UBERON:0001120	89.74	gold quality
cerebellum	UBERON:0002037	89.74	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting FZR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4483	98.09	64.12	1642

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Destruction-box specificities of APC/C(fzy) and APC/C(fzr)& successive activation of APC/C by fzy & fzr establish the temporal substrate degradation pattern, explaining why some endogenous RXXL substrates are degraded by fzy & others by fzr complexes. (PMID:12198152)
• Findings document the differential expression, subcellular localization and cell-cycle-regulatory activity of alternatively spliced human CDH1 isoforms. (PMID:12797865)
• Results indicate that Cdh1 mediates its own degradation by activating the anaphase-promoting complex/cyclosome to degrade itself. (PMID:15029244)
• upon infection of quiescent cells human cytomegalovirus not only activates the E2F-dependent G(1)/S transcription program but also facilitates protein accumulation of APC/C substrates by rapid Cdh1 dissociation (PMID:16138013)
• Cell cycle regulation of Six1 occurs both transcriptionally and post-translationally via phosphorylation (PMID:17130831)
• Cdh1/APC is crucial to the coordination of cell cycle progression and the initiation of lens differentiation through mediating TGF-beta-signaling-induced destruction of SnoN. (PMID:17215516)
• identify a novel mechanism for tumor suppression by TGF-beta and explain why dysfunction of APC in the TGF-beta pathway in responsive cells is associated with cancer. (PMID:17283060)
• Data show that degradation of TMAP/CKAP2 during mitotic exit is mediated by the anaphase-promoting complex bound to Cdh1 and that the KEN box motif near the N terminus is necessary for its destruction. (PMID:17339342)
• Acute UV radiation triggers proteolysis of CDH1, an activator of APC, which is involved in regulation of apoptosis induced by UV radiation. (PMID:18174259)
• Retinoic acid downregulates Rae1, hence facilitating APC(Cdh1)-mediated Skp2 degradation leading to the arrest of cell cycle progression and neuroblastoma differentiation. (PMID:18212744)
• during endocycles, APC/C Fzr/Cdh1 functions to reduce the levels of the mitotic cyclins and Geminin in order to facilitate the relicensing of DNA replication origins and cell cycle progression (PMID:18321983)
• Cdh1 may act as an important component in tumor suppression and could be considered as a novel biomarker in breast cancer. (PMID:18381934)
• Study shows a correlation between Skp2 and APC(Cdh1) in breast cancer. Cdh1 may act as an important component in tumor suppression and could be considered as a novel biomarker in breast cancer. (PMID:18381934)
• In response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/C(Cdh1), with the consequent degradation of Plk1, a prominent mitotic kinase. (PMID:18662541)
• Cdh1-dependent degradation of FoxM1 is required to shut down transcriptional activation of mitotic regulators during exit from mitosis. (PMID:18758239)
• Reduced Cdh1 levels have no effect on destruction of many APC/C substrates during mitotic exit but strongly and specifically stabilize Aurora kinases. (PMID:18976910)
• Low Cdh1 expression is associated with breast cancer. (PMID:19350629)
• Cdh1 reciprocally regulates the Rb pathway through competing with E2F1 to bind the hypophosphorylated form of Rb. (PMID:19477924)
• these findings suggest that Cdh1 controls TACC3 protein stability during mitotic exit. (PMID:19823035)
• FZR1 is not required for the completion of mitosis, but is an important regulator of G1 phase and is required for efficient DNA replication in human and mouse somatic cells. (PMID:19861496)
• Glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1. (PMID:20080744)
• DDB1 modulates the function of APC/C(Cdh1) in a manner independent of the Cul4-DDB1 complex (PMID:20395298)
• Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress (PMID:20424596)
• Cdh1-depleted HeLa cells reduced stress fiber formation significantly. The GTP-bound active Rho protein was apparently decreased in the Cdh1-depleted cells. (PMID:20530197)
• Data report that a nuclear-localized portion of the stress-activated kinase JNK is degraded by the APC/C(Cdh1) during exit from mitosis and the G1 phase of the cell cycle. (PMID:20581839)
• Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. (PMID:20686030)
• the sequential actions of the APC-c(Cdc20) and APC-c(Cdh1) ubiquitin ligases regulate the clearance of Mps1 levels and are critical for Mps1 functions during the cell cycle in human cells. (PMID:20729194)
• Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes. (PMID:20921411)
• Substrates are recruited to the Anaphase-promoting complex by binding to a bipartite substrate receptor composed of Cdh1 and Doc1. (PMID:21186364)
• Study shows that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. (PMID:21241890)
• APC/CCdh1 is a master G0/G1 regulator and involved in differentiation and development processes. (Review) (PMID:21497201)
• The deubiquitinase USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A. USP37 was induced by E2F factors in G1, peaked at G1/S, and was degraded in late mitosis. Phosphorylation of USP37 by CDK2 stimulated its full activity. (PMID:21596315)
• The Cells lacking Cdh1 have been shown to accumulate deoxyribonucleic acid (DNA) damage, suggesting that it may play a previously unrecognized role in maintaining genomic stability. (PMID:21768287)
• Ect2 is subject to proteasomal degradation after mitosis, following ubiquitination by the APC/C complex and its co-activator Cdh1 (PMID:21886810)
• studies uncover a cell-cycle-independent function of Cdh1, establishing Cdh1 as an upstream component that governs Smurf1 activity (PMID:22152476)
• In senescent cells, the DNA damage response induces proteasomal degradation of G9a and GLP, histone methyltransferases, through Cdc14B- and p21(Waf1/Cip1)-dependent activation of APC/C(Cdh1) ubiquitin ligase. (PMID:22178396)
• APC/C(Cdc20) or APC/C(Cdh1) complexes regulate RAP80 stability during mitosis to the G(1) phase, and these events are critical for a novel function of RAP80 in mitotic progression. (PMID:22426463)
• APC/CCdh1 is able to ubiquitylate E2F3A in vitro, and that the degradation of E2F3A is stimulated by Cdh1, but not by Cdc20. (PMID:22580460)
• The effect of Cdh1 on E2F1 degradation is blocked upon DNA damage. (PMID:22580462)
• Anaphase-promoting complex/cyclosome-CDH1, rather than Cdc20, promotes the degradation of BRSK2 in vivo. (PMID:23029325)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fzr1a	ENSDARG00000015254
mus_musculus	Fzr1	ENSMUSG00000020235
rattus_norvegicus	Fzr1	ENSRNOG00000004169
drosophila_melanogaster	fzr	FBGN0262699
caenorhabditis_elegans		WBGENE00001510

Paralogs (2): CDC20 (ENSG00000117399), CDC20B (ENSG00000164287)

Protein

Protein identifiers

Fizzy-related protein homolog — Q9UM11 (reviewed: Q9UM11)

Alternative names: CDC20-like protein 1, Cdh1/Hct1 homolog

All UniProt accessions (2): Q9UM11, K7EQT1

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR).

Subunit / interactions. The unphosphorylated form interacts with APC/C during mitosis. Interacts with NINL. Interacts (in complex with the anaphase promoting complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation. Interacts with SIRT2 and USP37. Interacts (via WD repeats) with MAK. Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation. Interacts with HECW2. Interacts with SASS6; the interaction is regulated by CENATAC and leads to SASS6 proteasomal degradation. Interacts (via N-terminus) with CCNF. Interacts with CDC6. Interacts with TK1 (via the KEN box).

Subcellular location. Nucleus Cytoplasm.

Tissue specificity. Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.

Post-translational modifications. Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159; deacetylation enhances the interaction of FZR1 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C). Following DNA damage, it is dephosphorylated by CDC14B in G2 phase, leading to its reassociation with the APC/C, and allowing an efficient G2 DNA damage checkpoint. Phosphorylated by MAK. Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.

Disease relevance. Developmental and epileptic encephalopathy 109 (DEE109) [MIM:620145] A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE109 is an autosomal dominant form characterized by the onset of various types of seizures in the first months or years of life. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Major. Minor.

Similarity. Belongs to the WD repeat CDC20/Fizzy family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UM11-1	1	yes
Q9UM11-2	2, CDH1alpha, Fzr1
Q9UM11-3	3, CDH1beta, Fzr2

RefSeq proteins (3): NP_001129669, NP_001129670, NP_057347* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR033010	Cdc20/Fizzy	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR056150	WD40_CDC20-Fz	Domain

Pfam: PF24807

UniProt features (89 total): strand 35, modified residue 8, mutagenesis site 8, repeat 7, helix 7, turn 6, region of interest 4, compositionally biased region 4, sequence conflict 4, sequence variant 3, splice variant 2, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9GAW	ELECTRON MICROSCOPY	2.9
8TAU	ELECTRON MICROSCOPY	3.5
4UI9	ELECTRON MICROSCOPY	3.6
8TAR	ELECTRON MICROSCOPY	4
5L9T	ELECTRON MICROSCOPY	6.4
5L9U	ELECTRON MICROSCOPY	6.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM11-F1	82.24	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 32, 36, 69, 133, 138, 146, 151, 159

Mutagenesis-validated functional residues (8):

Position	Phenotype
7–14	reduced interaction with ccnf. impaired degradation.
40	constitutively active; when associated with a-121; a-151 and a-163. does not affect apc/fzr1 e3 ubiquitin-protein ligase
47	inhibits apc/fzr1 e3 ubiquitin-protein ligase complex activity.
52	inhibits apc/fzr1 e3 ubiquitin-protein ligase complex activity.
121	constitutively active; when associated with a-40; a-151 and a-163. does not affect apc/fzr1 e3 ubiquitin-protein ligase
151	constitutively active; when associated with a-40; a-121 and a-163. does not affect ubiquitination; when associated with
163	constitutively active; when associated with a-40; a-121 and a-151. does not affect apc/fzr1 e3 ubiquitin-protein ligase
445–447	reduced interaction with ccnf.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-176407	Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176417	Phosphorylation of Emi1
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6
R-HSA-69273	Cyclin A/B1/B2 associated events during G2/M transition
R-HSA-69656	Cyclin A:Cdk2-associated events at S phase entry
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-9687136	Aberrant regulation of mitotic exit in cancer due to RB1 defects
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 1052 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, REACTOME_DNA_REPLICATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, FARMER_BREAST_CANCER_CLUSTER_7, REACTOME_CONVERSION_FROM_APC_C_CDC20_TO_APC_C_CDH1_IN_LATE_ANAPHASE, GU_PDEF_TARGETS_DN, chr16q22, GOBP_NEURON_PROJECTION_EXTENSION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION

GO Biological Process (18): DNA repair (GO:0006281), mitotic G2 DNA damage checkpoint signaling (GO:0007095), regulation of mitotic cell cycle (GO:0007346), positive regulation of cell population proliferation (GO:0008284), anaphase-promoting complex-dependent catabolic process (GO:0031145), regulation of meiotic nuclear division (GO:0040020), cell division (GO:0051301), regulation of meiotic cell cycle (GO:0051445), lens fiber cell differentiation (GO:0070306), protein K11-linked ubiquitination (GO:0070979), positive regulation of ubiquitin protein ligase activity (GO:1904668), positive regulation of anaphase-promoting complex-dependent catabolic process (GO:1905786), negative regulation of cellular senescence (GO:2000773), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), thymidine biosynthetic process (GO:0046105), obsolete proteolysis involved in protein catabolic process (GO:0051603), DNA synthesis involved in mitotic DNA replication (GO:1904860)

GO Molecular Function (5): anaphase-promoting complex binding (GO:0010997), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), ubiquitin ligase activator activity (GO:1990757), protein binding (GO:0005515), ubiquitin-protein transferase activator activity (GO:0097027)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), anaphase-promoting complex (GO:0005680), cytosol (GO:0005829), nuclear membrane (GO:0031965), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
APC/C-mediated degradation of cell cycle proteins	4
Regulation of APC/C activators between G1/S and early anaphase	2
Cellular Senescence	1
DNA Replication Pre-Initiation	1
Switching of origins to a post-replicative state	1
G2/M Transition	1
S Phase	1
Generic Transcription Pathway	1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of cell cycle	2
DNA metabolic process	1
DNA damage response	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
mitotic cell cycle	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of cell cycle process	1
regulation of meiotic cell cycle	1
regulation of nuclear division	1
meiotic nuclear division	1
cellular process	1
meiotic cell cycle	1
regulation of reproductive process	1
lens development in camera-type eye	1
epithelial cell differentiation	1
protein polyubiquitination	1
positive regulation of ubiquitin-protein transferase activity	1
ubiquitin protein ligase activity	1
regulation of ubiquitin protein ligase activity	1
anaphase-promoting complex-dependent catabolic process	1
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1
regulation of anaphase-promoting complex-dependent catabolic process	1
negative regulation of cellular process	1
cellular senescence	1
regulation of cellular senescence	1
cellular response to stress	1
protein modification by small protein conjugation	1
thymidine metabolic process	1
pyrimidine deoxyribonucleoside biosynthetic process	1
DNA synthesis involved in DNA replication	1
mitotic DNA replication	1
mitotic cell cycle process	1
protein-containing complex binding	1
enzyme-substrate adaptor activity	1

Protein interactions and networks

STRING

4175 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FZR1	ANAPC2	Q9UJX6	967
FZR1	CDC27	P30260	942
FZR1	BUB3	O43684	855
FZR1	BUB1B	O60566	813
FZR1	ANAPC10	Q9UM13	798
FZR1	CDC23	Q9UJX2	765
FZR1	CDC16	Q13042	741
FZR1	ANAPC5	Q9UJX4	717
FZR1	ANAPC11	Q9NYG5	715
FZR1	CCNA2	P20248	699
FZR1	PTTG1	O95997	696
FZR1	CCNB1	P14635	681
FZR1	CDK1	P06493	670
FZR1	PLK1	P53350	649
FZR1	PTTG2	Q9NZH5	629

IntAct

127 interactions, top by confidence:

A	B	Type	Score
ANAPC2	CDC27	psi-mi:“MI:0915”(physical association)	0.910
CDC27	FZR1	psi-mi:“MI:0915”(physical association)	0.910
FZR1	CDC27	psi-mi:“MI:0915”(physical association)	0.910
FZR1	CDC27	psi-mi:“MI:0914”(association)	0.910
ANAPC4	CDC27	psi-mi:“MI:0914”(association)	0.860
RRM2	RRM1	psi-mi:“MI:0914”(association)	0.850
CDC16	BUB1B	psi-mi:“MI:0914”(association)	0.790
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
ANAPC16	BUB1B	psi-mi:“MI:0914”(association)	0.730
ANAPC2	BUB1B	psi-mi:“MI:0914”(association)	0.730
SRP68	SRP72	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RRM2	FZR1	psi-mi:“MI:0915”(physical association)	0.710
CDC27	FBXO5	psi-mi:“MI:0914”(association)	0.670
CDCA3	CTDSPL	psi-mi:“MI:0914”(association)	0.670
SKP2	FZR1	psi-mi:“MI:0915”(physical association)	0.670
FZR1	CLSPN	psi-mi:“MI:0915”(physical association)	0.640

BioGRID (1593): CCNB1 (Biochemical Activity), FZR1 (Reconstituted Complex), CCNB1 (Biochemical Activity), PTTG1 (Biochemical Activity), TP53 (Biochemical Activity), ZC3HC1 (Biochemical Activity), FZR1 (Affinity Capture-Western), CDR2 (Biochemical Activity), CCNB1 (Biochemical Activity), CCNB1 (Reconstituted Complex), PTTG1 (Reconstituted Complex), CDC25A (Reconstituted Complex), CCNB1 (Reconstituted Complex), RBBP8 (Affinity Capture-Western), FZR1 (Reconstituted Complex)

ESM2 similar proteins: A0A396ISC0, O00423, O13286, O17468, O61585, O94423, P26309, P38328, P43254, P53197, P78972, P93471, Q04199, Q05BC3, Q09373, Q12834, Q16MY0, Q2TAF3, Q32SG6, Q3E906, Q4PSE4, Q4V7Y7, Q4V8C3, Q54MZ3, Q5H7C0, Q5ZIU8, Q62623, Q652L2, Q6DIP5, Q6NVM2, Q6S7B0, Q7K0L4, Q7ZUV2, Q7ZVL2, Q7ZX22, Q86Y33, Q8BG40, Q8CFJ9, Q8L3Z8, Q8LPL5

Diamond homologs: A0A1L8I2C5, A0A396ISC0, D3Z3I0, F4K5R6, O13286, O65418, O94423, P26309, P53197, P78972, Q12834, Q1HPW4, Q3E906, Q4PSE4, Q54KM3, Q54MZ3, Q5H7C0, Q62623, Q86Y33, Q8L3Z8, Q8LPL5, Q8VZS9, Q9FN19, Q9JJ66, Q9M7I2, Q9R1K5, Q9S7H3, Q9S7I8, Q9SZA4, Q9UM11, A3LQ86, O94411, O94620, P25387, Q09786, Q15269, Q5RFQ3, Q8NEZ3, Q93134, Q9P783

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
FBXO5	down-regulates	FZR1	ubiquitination
PIM1	“down-regulates activity”	FZR1	phosphorylation
USP37	“down-regulates activity”	FZR1	binding
FZR1	“up-regulates activity”	UBE2S	binding
CCNF	“down-regulates quantity by destabilization”	FZR1	ubiquitination
FZR1	“down-regulates quantity by destabilization”	CDC25A	ubiquitination
FZR1	“down-regulates quantity by destabilization”	PFKFB3	binding
FZR1	“down-regulates quantity by destabilization”	SKIL	binding
FZR1	“down-regulates quantity by destabilization”	DTYMK	binding
FZR1	“down-regulates quantity by destabilization”	ANLN	binding
FZR1	“down-regulates quantity by destabilization”	REV1	binding
FZR1	“up-regulates activity”	APC-c	binding
FZR1	“down-regulates quantity by destabilization”	MOAP1	binding
FZR1	“down-regulates quantity”	DNM1L	ubiquitination
CDK2	“down-regulates activity”	FZR1	phosphorylation
MAD2L2	“down-regulates activity”	FZR1	binding
FZR1	“down-regulates quantity by destabilization”	AURKA	binding
FZR1	“down-regulates quantity by destabilization”	TK1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	11	114.4×	6e-20
Phosphorylation of the APC/C	12	107.0×	4e-21
Inactivation of APC/C via direct inhibition of the APC/C complex	12	102.1×	7e-21
APC/C-mediated degradation of cell cycle proteins	17	93.6×	1e-28
Regulation of mitotic cell cycle	17	93.6×	1e-28
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	14	93.6×	1e-23
Aberrant regulation of mitotic exit in cancer due to RB1 defects	11	93.6×	1e-18
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	13	90.1×	1e-21

GO biological processes:

GO term	Partners	Fold	FDR
protein branched polyubiquitination	10	120.4×	3e-17
anaphase-promoting complex-dependent catabolic process	11	110.3×	2e-18
regulation of meiotic cell cycle	10	109.4×	9e-17
protein K11-linked ubiquitination	11	61.6×	2e-15
positive regulation of G2/M transition of mitotic cell cycle	5	43.0×	5e-06
regulation of mitotic cell cycle	12	41.3×	1e-14
protein K48-linked ubiquitination	12	28.9×	8e-13
G2/M transition of mitotic cell cycle	5	22.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

82 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	45
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1802183	NM_016263.4(FZR1):c.560A>G (p.Asp187Gly)	Pathogenic
1802185	NM_016263.4(FZR1):c.999C>G (p.Asn333Lys)	Pathogenic
1802186	NM_016263.4(FZR1):c.999C>A (p.Asn333Lys)	Pathogenic
3097716	NM_016263.4(FZR1):c.946G>C (p.Val316Leu)	Likely pathogenic

SpliceAI

2814 predictions. Top by Δscore:

Variant	Effect	Δscore
19:3522950:CTGCA:C	acceptor_loss	1.0000
19:3522951:TGCA:T	acceptor_loss	1.0000
19:3522952:GCAG:G	acceptor_loss	1.0000
19:3522953:CAG:C	acceptor_loss	1.0000
19:3522954:A:AG	acceptor_gain	1.0000
19:3522954:AGGC:A	acceptor_loss	1.0000
19:3522955:G:GA	acceptor_gain	1.0000
19:3523057:GC:G	donor_gain	1.0000
19:3523059:G:GG	donor_gain	1.0000
19:3525970:A:T	donor_gain	1.0000
19:3525987:GAT:G	donor_gain	1.0000
19:3525994:G:GG	donor_gain	1.0000
19:3526119:GGA:G	acceptor_gain	1.0000
19:3526387:G:GG	donor_gain	1.0000
19:3526387:GTA:G	donor_loss	1.0000
19:3526388:T:A	donor_loss	1.0000
19:3526978:A:AG	acceptor_gain	1.0000
19:3526979:G:GA	acceptor_gain	1.0000
19:3526979:GT:G	acceptor_gain	1.0000
19:3526979:GTATT:G	acceptor_gain	1.0000
19:3527629:A:AG	acceptor_gain	1.0000
19:3527630:G:GA	acceptor_gain	1.0000
19:3527630:GCCA:G	acceptor_gain	1.0000
19:3527810:GCCAG:G	donor_gain	1.0000
19:3527811:CCAGG:C	donor_loss	1.0000
19:3527812:CAGGT:C	donor_loss	1.0000
19:3527815:GT:G	donor_loss	1.0000
19:3527816:T:G	donor_loss	1.0000
19:3532030:G:GT	donor_gain	1.0000
19:3532091:ACAAG:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014402 (19:3529253 G>GGA), RS1000016625 (19:3532884 C>G,T), RS1000042985 (19:3537444 C>T), RS1000104529 (19:3524876 C>A,T), RS1000115939 (19:3520034 C>A), RS1000191762 (19:3517623 G>C), RS1000226158 (19:3517376 T>C), RS1000387570 (19:3533045 G>A,T), RS1000478107 (19:3527317 T>A), RS1000526168 (19:3519003 G>A), RS1000557029 (19:3518681 A>G), RS1000724399 (19:3520978 C>G,T), RS1000770949 (19:3511607 T>G), RS1000777558 (19:3522816 G>T), RS1000780461 (19:3525628 G>C,T)

Disease associations

OMIM: gene MIM:603619 | disease phenotypes: MIM:209850, MIM:620145

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy 109	Strong	Autosomal dominant

Mondo (3): cerebellar ataxia (MONDO:0000437), autism (MONDO:0005260), developmental and epileptic encephalopathy 109 (MONDO:0859325)

Orphanet (1): Rare ataxia (Orphanet:102002)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001315	Reduced tendon reflexes
HP:0001336	Myoclonus
HP:0001337	Tremor

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002404_551	Red cell distribution width	8.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523493 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases oxidation, affects expression, decreases expression, affects cotreatment, increases abundance	3
Benzo(a)pyrene	decreases methylation, increases expression	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment	2
Valproic Acid	increases expression, increases methylation	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenite	increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
lactacystin	affects localization, decreases reaction	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects methylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diazinon	decreases methylation	1
Estradiol	increases expression, affects localization, decreases expression, decreases reaction, affects cotreatment	1
Progesterone	affects cotreatment, increases expression, affects localization, decreases reaction	1
Selenium	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Vitamin E	affects cotreatment, increases expression	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4406132	Binding	Inhibition of CDH1 in human HepG2 cells assessed as effect on Aurora A protein expression at 30 uM incubated for 48 hrs by Western blot Analysis	Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2XG	Abcam HEK293T FZR1 KO	Transformed cell line	Female
CVCL_D7QD	Ubigene A-549 FZR1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration