UFL1

Summary

UFL1 (UFM1 specific ligase 1, HGNC:23039) is a protein-coding gene on chromosome 6q16.1, encoding E3 UFM1-protein ligase 1 (O94874). E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophag…. It is a selective cancer dependency (DepMap: 35.4% of cell lines).

Enables UFM1 ligase activity and protein kinase binding activity. Involved in several processes, including positive regulation of reticulophagy; regulation of intracellular signal transduction; and regulation of primary metabolic process. Acts upstream of or within several processes, including positive regulation of cell population proliferation; regulation of proteasomal ubiquitin-dependent protein catabolic process; and response to endoplasmic reticulum stress. Located in cytoplasm; nucleus; and site of double-strand break. Part of protein-containing complex. Is active in endoplasmic reticulum membrane and mitochondrial outer membrane.

Source: NCBI Gene 23376 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 150 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 35.4% of screened cell lines
• MANE Select transcript: NM_015323

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23039
Approved symbol	UFL1
Name	UFM1 specific ligase 1
Location	6q16.1
Locus type	gene with protein product
Status	Approved
Aliases	NLBP, Maxer, RCAD
Ensembl gene	ENSG00000014123
Ensembl biotype	protein_coding
OMIM	613372
Entrez	23376

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000369278, ENST00000461673, ENST00000863355, ENST00000863356, ENST00000946281

RefSeq mRNA: 1 — MANE Select: NM_015323 NM_015323

CCDS: CCDS5034

Canonical transcript exons

ENST00000369278 — 19 exons

Exon	Start	End
ENSE00000760828	96549669	96549799
ENSE00000760830	96551838	96551923
ENSE00000760831	96552482	96552662
ENSE00000840202	96538631	96538810
ENSE00000840203	96540535	96540655
ENSE00000840204	96542894	96543016
ENSE00000840205	96548164	96548281
ENSE00000840208	96549412	96549578
ENSE00000840210	96551433	96551513
ENSE00000974812	96523146	96523291
ENSE00000974813	96525297	96525394
ENSE00000974814	96526321	96526435
ENSE00000974815	96528502	96528632
ENSE00000974816	96534263	96534321
ENSE00000974817	96536244	96536390
ENSE00000974818	96537374	96537549
ENSE00001004307	96524382	96524410
ENSE00001383721	96553285	96555276
ENSE00001449377	96521806	96521950

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 96.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.6315 / max 501.0819, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68936	39.6315	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	96.35	gold quality
corpus epididymis	UBERON:0004359	95.88	gold quality
calcaneal tendon	UBERON:0003701	95.45	gold quality
germinal epithelium of ovary	UBERON:0001304	95.33	gold quality
secondary oocyte	CL:0000655	95.09	gold quality
cauda epididymis	UBERON:0004360	95.03	gold quality
epithelium of nasopharynx	UBERON:0001951	94.91	gold quality
blood vessel layer	UBERON:0004797	94.63	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.59	gold quality
oocyte	CL:0000023	94.30	gold quality
oral cavity	UBERON:0000167	94.16	gold quality
superficial temporal artery	UBERON:0001614	94.16	gold quality
gingival epithelium	UBERON:0001949	94.16	gold quality
jejunum	UBERON:0002115	93.79	gold quality
jejunal mucosa	UBERON:0000399	93.69	gold quality
skin of hip	UBERON:0001554	93.46	gold quality
palpebral conjunctiva	UBERON:0001812	93.45	gold quality
corpus callosum	UBERON:0002336	93.25	gold quality
choroid plexus epithelium	UBERON:0003911	93.21	gold quality
parietal pleura	UBERON:0002400	93.18	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.18	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.83	gold quality
biceps brachii	UBERON:0001507	92.81	gold quality
superior surface of tongue	UBERON:0007371	92.80	gold quality
gingiva	UBERON:0001828	92.71	gold quality
tibia	UBERON:0000979	92.58	gold quality
upper leg skin	UBERON:0004262	92.54	gold quality
pleura	UBERON:0000977	92.38	gold quality
adrenal tissue	UBERON:0018303	92.15	gold quality
penis	UBERON:0000989	92.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting UFL1, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 35.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• Results identify a novel molecule named multiple alpha-helix protein located at ER (Maxer) downregulated by mutant ataxin-1 (Atx1) in Bergmann glia. (PMID:20531390)
• Overexpression of NLBP promotes the cell proliferation of lung adenocarcinoma through interacting with p120ctn. (PMID:23839039)
• Study findings reveal that ufmylation of histone H4 by UFL1 is an important step for amplification of ATM activation and maintenance of genomic integrity. (PMID:30886146)
• UFL1 attenuates IL-1beta-induced inflammatory response in human osteoarthritis chondrocytes. (PMID:32050156)
• Signaling from the RNA sensor RIG-I is regulated by ufmylation. (PMID:35394863)
• Ubiquitin-like modifier 1 ligating enzyme 1 relieves cisplatin-induced premature ovarian failure by reducing endoplasmic reticulum stress in granulosa cells. (PMID:35610622)
• UFL1 alleviates ER stress and apoptosis stimulated by LPS via blocking the ferroptosis pathway in human granulosa-like cells. (PMID:35729487)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ufl1	ENSDARG00000007496
mus_musculus	Ufl1	ENSMUSG00000040359
rattus_norvegicus	Ufl1	ENSRNOG00000007831
drosophila_melanogaster	Ufl1	FBGN0037467
caenorhabditis_elegans		WBGENE00015555

Protein

Protein identifiers

E3 UFM1-protein ligase 1 — O94874 (reviewed: O94874)

Alternative names: E3 UFM1-protein transferase 1, Multiple alpha-helix protein located at ER, Novel LZAP-binding protein, Regulator of C53/LZAP and DDRGK1

All UniProt accessions (1): O94874

UniProt curated annotations — full annotation on UniProt →

Function. E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy). Catalyzes ufmylation of many protein, such as CD274/PD-L1, CDK5RAP3, CYB5R3, DDRGK1, EIF6, histone H4, MRE11, P4HB, PDCD1/PD-1, TRIP4, RPN1, RPS20/uS10, RPL10/uL16, RPL26/uL24, SYVN1/HRD1 and TP53/p53. As part of the UREL complex, plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome. Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane. Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum. Involved in reticulophagy in response to endoplasmic reticulum stress by mediating ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins. Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response. Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is, a collateral effect or is required for ufmylation. Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1. Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 and ufmylation of MRE11. Mediates ufmylation of TP53/p53, promoting its stability. Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription. Required for hematopoietic stem cell function and hematopoiesis.

Subunit / interactions. Catalytic component of the UFM1 ribosome E3 ligase (UREL) complex, composed of UFL1, DDRGK1 and CDK5RAP3. Interacts with E2-like enzyme UFC1. Interacts with RELA. Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage. Interacts (when phosphorylated) with YWHAG/14-3-3-gamma; sequestering UFL1 and preventing its association with PDCD1/PD-1 substrate. (Microbial infection) Interacts with Epstein-Barr virus protein BILF1; this interaction mediates MAVS UFMylation and subsequent routing from mitochondria to lysosomes.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasm. Cytosol. Nucleus. Chromosome.

Tissue specificity. Ubiquitously expressed, with a high expression in liver (at protein level). Low expression in several invasive hepatocellular carcinomas, such Hep-G2, Hep 3B2.1-7, HLE and PLC.

Post-translational modifications. Ubiquitinated, leading to its degradation by the proteasome. Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome. Phosphorylated at Ser-462 by ATM, enhancing protein ligase activity and promoting ATM activation in a positive feedback loop. Phosphorylation at Thr-536 by AMPK promotes its interaction with YWHAG/14-3-3-gamma, thereby preventing UFL1 association with PDCD1/PD-1 substrate.

Induction. Up-regulated by thapsigargin. Down-regulated in the failing hearts of patients with dilated cardiomyopathy.

Similarity. Belongs to the UFL1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O94874-1	1	yes
O94874-2	2
O94874-3	3

RefSeq proteins (1): NP_056138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018611	Ufl1	Family
IPR056579	Ufl1_N	Domain
IPR056580	Ufl1_dom	Domain
IPR056761	Ufl1-like_C	Domain

Pfam: PF09743, PF23659, PF25041, PF25870

UniProt features (90 total): helix 34, mutagenesis site 19, strand 15, region of interest 7, modified residue 5, turn 4, splice variant 3, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8QFD	ELECTRON MICROSCOPY	2.2
8C0D	X-RAY DIFFRACTION	2.56
8OJ5	ELECTRON MICROSCOPY	2.9
9GY4	ELECTRON MICROSCOPY	3
8B9X	X-RAY DIFFRACTION	3.07
8OHD	ELECTRON MICROSCOPY	3.1
8QFC	ELECTRON MICROSCOPY	3.2
8OJ0	ELECTRON MICROSCOPY	3.3
8OJ8	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94874-F1	80.80	0.39

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 (5): 433, 458, 462, 536, 2

Mutagenesis-validated functional residues (19):

Position	Phenotype
8	abolished interaction with e2-like enzyme ufc1.
11–15	abolished interaction with e2-like enzyme ufc1.
15	abolished interaction with e2-like enzyme ufc1.
19	abolished interaction with e2-like enzyme ufc1.
27	abolished interaction with ddrgk1; when associated with a-32–a-39.
32–39	abolished interaction with ddrgk1; when associated with a-27.
32	does not affect ufm1 ligase activity.
125–127	abolished interaction with ufc1, impairing e3 protein ligase activity and ability to regulate atm activation.
129	abolished interaction with cdk5rap3; when associated with a-185, a-191, a-199 and a-251.
143	does not affect ufm1 ligase activity.
185	abolished interaction with cdk5rap3; when associated with a-129, a-191, a-199 and a-251.
191	abolished interaction with cdk5rap3; when associated with a-129, a-185, a-199 and a-251.
199	abolished interaction with cdk5rap3; when associated with a-129, a-185, a-191 and a-251.
251	abolished interaction with cdk5rap3; when associated with a-129, a-185, a-191 and a-199.
300	does not affect ufm1 ligase activity.
372	does not affect ufm1 ligase activity.
462	impaired recruitment to double-strand break sites.
536	abolished phosphorylation by ampk, preventing interaction with ywhag/14-3-3-gamma and promoting pdcd1/pd-1 ufmylation.
536	mimics phosphorylation; leading to decreased pdcd1/pd-1 ufmylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 293 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOBP_MYELOID_CELL_HOMEOSTASIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (41): DNA damage checkpoint signaling (GO:0000077), osteoblast differentiation (GO:0001649), negative regulation of T cell mediated immune response to tumor cell (GO:0002841), DNA repair (GO:0006281), DNA damage response (GO:0006974), positive regulation of cell population proliferation (GO:0008284), positive regulation of autophagy (GO:0010508), erythrocyte differentiation (GO:0030218), negative regulation of protein ubiquitination (GO:0031397), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), ribosome disassembly (GO:0032790), regulation of protein localization (GO:0032880), regulation of intracellular estrogen receptor signaling pathway (GO:0033146), response to endoplasmic reticulum stress (GO:0034976), regulation of canonical NF-kappaB signal transduction (GO:0043122), regulation of inflammatory response (GO:0050727), protein stabilization (GO:0050821), negative regulation of T cell activation (GO:0050868), hematopoietic stem cell differentiation (GO:0060218), positive regulation of glial cell proliferation (GO:0060252), reticulophagy (GO:0061709), protein ufmylation (GO:0071569), rescue of stalled cytosolic ribosome (GO:0072344), positive regulation of reticulophagy (GO:0140501), response to L-glutamate (GO:1902065), obsolete positive regulation of proteolysis involved in protein catabolic process (GO:1903052), negative regulation of IRE1-mediated unfolded protein response (GO:1903895), protein K69-linked ufmylation (GO:1990592), double-strand break repair via homologous recombination (GO:0000724), DNA double-strand break processing (GO:0000729), positive regulation of T cell mediated immune response to tumor cell (GO:0002842), blood circulation (GO:0008015), regulation of gene expression (GO:0010468), DNA damage response, signal transduction by p53 class mediator (GO:0030330), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), NLRP3 inflammasome complex assembly (GO:0044546), positive regulation of T cell activation (GO:0050870), antiviral innate immune response (GO:0140374)

GO Molecular Function (5): protein kinase binding (GO:0019901), UFM1 ligase activity (GO:0061666), UFM1 transferase activity (GO:0071568), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (11): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), protein-containing complex (GO:0032991), site of double-strand break (GO:0035861), neuron projection (GO:0043005), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
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
cellular response to stress	2
intracellular membrane-bounded organelle	2
cytoplasm	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
ossification	1
cell differentiation	1
T cell mediated immune response to tumor cell	1
negative regulation of T cell mediated immunity	1
negative regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
DNA metabolic process	1
DNA damage response	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
organelle disassembly	1
intracellular protein localization	1
regulation of localization	1
estrogen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of intracellular signal transduction	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
regulation of protein stability	1
T cell activation	1

Protein interactions and networks

STRING

2552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UFL1	CDK5RAP3	Q96JB5	999
UFL1	DDRGK1	Q96HY6	977
UFL1	UFM1	P61960	943
UFL1	UBA5	Q9GZZ9	934
UFL1	UFC1	Q9Y3C8	873
UFL1	UFSP2	Q9NUQ7	859
UFL1	UFSP1	Q6NVU6	808
UFL1	MMP9	P14780	589
UFL1	CDK5	Q00535	586
UFL1	TRIP4	Q15650	574
UFL1	GABARAP	O95166	518
UFL1	RPL26	P61254	506
UFL1	UEVLD	Q8IX04	460
UFL1	MOCS3	O95396	442
UFL1	EIF6	P56537	428

IntAct

143 interactions, top by confidence:

A	B	Type	Score
UFL1	CDK5RAP3	psi-mi:“MI:0915”(physical association)	0.870
CDK5RAP3	UFL1	psi-mi:“MI:0407”(direct interaction)	0.870
CDK5RAP3	UFL1	psi-mi:“MI:0914”(association)	0.870
UFL1	CDK5RAP3	psi-mi:“MI:0914”(association)	0.870
UFC1	UFL1	psi-mi:“MI:0407”(direct interaction)	0.720
UFC1	UFL1	psi-mi:“MI:0914”(association)	0.720
UFL1	UFC1	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UFL1	DDRGK1	psi-mi:“MI:0914”(association)	0.710
DDRGK1	UFL1	psi-mi:“MI:0914”(association)	0.710
DDRGK1	UFL1	psi-mi:“MI:0915”(physical association)	0.710
UFL1	DDRGK1	psi-mi:“MI:0915”(physical association)	0.710
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
CDK5RAP3	PLD2	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
USP1	UFL1	psi-mi:“MI:0407”(direct interaction)	0.440
UFL1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
UFL1	H2BC5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1145): UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Proximity Label-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), UFL1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4I9, A5D796, A5PJZ5, A7S2N8, A9ULY7, B0F9L4, B2GV24, F4HQ84, F4IDS7, O60308, O75694, O75717, O94874, P32780, P37199, P59328, Q14CX7, Q1RMS6, Q28HX4, Q4R367, Q5R822, Q5RBW9, Q5ZL91, Q5ZMG1, Q66HC5, Q6DDM4, Q6NX12, Q6P3X3, Q6PGY6, Q7TQK1, Q7ZU29, Q7ZX96, Q8BGQ1, Q8BJ71, Q8BWZ3, Q8CCJ3, Q8JGR7, Q8N1F7, Q8R3N6, Q8WVM7

Diamond homologs: A1A4I9, A7S2N8, B0WU24, B2GV24, B3LYC0, B3P2S2, B3RYG4, B4GEL3, B4I4N0, B4JV25, B4KDK5, B4LZW7, B4NAB3, B4PS24, B4QYZ3, O94874, Q0IG18, Q296V2, Q4R367, Q54QS0, Q5ZMG1, Q6PGY6, Q7Q373, Q8CCJ3, Q9VI55, A8WN14

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
UFL1	“up-regulates activity”	H4C1	ubiquitination
UFL1	“up-regulates activity”	ATM	ubiquitination
MRE11/RAD50/NBS1	“up-regulates activity”	UFL1	relocalization
ATM	“up-regulates activity”	UFL1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	6	20.5×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein K48-linked ubiquitination	7	8.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2936 predictions. Top by Δscore:

Variant	Effect	Δscore
6:96523142:TCA:T	acceptor_loss	1.0000
6:96523143:CAG:C	acceptor_loss	1.0000
6:96523144:A:AG	acceptor_gain	1.0000
6:96523144:AGGT:A	acceptor_loss	1.0000
6:96523145:G:GG	acceptor_gain	1.0000
6:96523145:G:GT	acceptor_loss	1.0000
6:96523145:GGTT:G	acceptor_gain	1.0000
6:96523287:AGGTG:A	donor_gain	1.0000
6:96523288:GGTGG:G	donor_gain	1.0000
6:96523289:GTG:G	donor_gain	1.0000
6:96523293:T:G	donor_loss	1.0000
6:96525291:TTCCA:T	acceptor_loss	1.0000
6:96525292:TCCA:T	acceptor_loss	1.0000
6:96525293:CCA:C	acceptor_loss	1.0000
6:96525294:CA:C	acceptor_loss	1.0000
6:96525295:A:AC	acceptor_loss	1.0000
6:96525296:GGTA:G	acceptor_gain	1.0000
6:96525390:GATGA:G	donor_gain	1.0000
6:96525391:A:G	donor_gain	1.0000
6:96525391:ATGA:A	donor_gain	1.0000
6:96525392:TGA:T	donor_gain	1.0000
6:96525392:TGAGT:T	donor_loss	1.0000
6:96525393:GA:G	donor_gain	1.0000
6:96525393:GAG:G	donor_gain	1.0000
6:96525393:GAGTA:G	donor_loss	1.0000
6:96525394:AGT:A	donor_loss	1.0000
6:96525395:G:GG	donor_gain	1.0000
6:96525395:GTAA:G	donor_loss	1.0000
6:96525396:T:A	donor_loss	1.0000
6:96525397:A:AG	donor_loss	1.0000

AlphaMissense

5238 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:96551438:A:C	R608S	0.999
6:96551438:A:T	R608S	0.999
6:96552622:T:A	V709D	0.999
6:96521905:T:C	L11S	0.998
6:96521907:G:C	A12P	0.998
6:96523148:T:C	L27S	0.998
6:96523175:T:A	V36D	0.998
6:96524385:G:C	R76P	0.998
6:96524403:T:C	L82P	0.998
6:96526413:T:C	L148P	0.998
6:96536325:C:A	P246H	0.998
6:96551437:G:C	R608T	0.998
6:96552523:T:C	L676P	0.998
6:96553322:T:A	V735D	0.998
6:96521917:T:C	F15S	0.997
6:96549560:G:A	G557R	0.997
6:96549560:G:C	G557R	0.997
6:96549560:G:T	G557W	0.997
6:96549713:T:C	C578R	0.997
6:96549715:T:G	C578W	0.997
6:96552482:A:C	R662S	0.997
6:96552482:A:T	R662S	0.997
6:96552502:G:C	R669P	0.997
6:96552553:T:C	L686P	0.997
6:96552555:C:G	H687D	0.997
6:96552559:T:C	L688P	0.997
6:96521910:G:C	A13P	0.996
6:96525385:T:C	L114P	0.996
6:96526362:T:C	L131S	0.996
6:96528610:G:A	G192R	0.996

dbSNP variants (sampled 300 via entrez): RS1000006155 (6:96547893 T>C), RS1000031366 (6:96533443 A>G), RS1000078255 (6:96547029 A>G), RS1000220834 (6:96534974 T>G), RS1000436111 (6:96521691 G>A,C), RS1000449210 (6:96542827 A>G), RS1000558548 (6:96536668 T>A,C), RS1000633492 (6:96536966 C>T), RS1000677380 (6:96545313 T>A), RS1000809203 (6:96524162 T>C), RS1000809800 (6:96552730 A>G), RS1000950850 (6:96525965 A>T), RS1001075796 (6:96530075 T>G), RS1001083362 (6:96543809 T>G), RS1001109525 (6:96545652 A>T)

Disease associations

OMIM: gene MIM:613372 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003542_90	Night sleep phenotypes	6.000000e-08
GCST003542_91	Night sleep phenotypes	1.000000e-08
GCST003720_16	Migraine	6.000000e-10
GCST003720_22	Migraine	2.000000e-27
GCST003721_4	Migraine without aura	1.000000e-12
GCST005337_2	Headache	3.000000e-31
GCST007095_111	Systolic blood pressure	3.000000e-08
GCST007095_112	Systolic blood pressure	5.000000e-07
GCST007096_241	Pulse pressure	4.000000e-07
GCST007098_13	Diastolic blood pressure	9.000000e-06
GCST007098_14	Diastolic blood pressure	1.000000e-06
GCST007099_178	Systolic blood pressure	5.000000e-10
GCST010244_115	Triglyceride levels	9.000000e-09
GCST011122_60	Walking pace	3.000000e-09
GCST90093325_10	Language functional connectivity	7.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0004530	triglyceride measurement
EFO:0007797	language measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066996 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.78	Kd	16.48	nM	CHEMBL5653589
7.78	ED50	16.48	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149723: Binding affinity to human UFL1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0165	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Cyclosporine	increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Calcitriol	increases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652765	Binding	Binding affinity to human UFL1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KT	Abcam HEK293T UFL1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome