URM1

Summary

URM1 (ubiquitin related modifier 1, HGNC:28378) is a protein-coding gene on chromosome 9q34.11, encoding Ubiquitin-related modifier 1 (Q9BTM9). Acts as a sulfur carrier required for 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln). It is a selective cancer dependency (DepMap: 80.2% of cell lines).

Enables sulfur carrier activity. Involved in tRNA thio-modification and tRNA wobble uridine modification. Predicted to be located in cytosol. Predicted to be active in nucleus.

Source: NCBI Gene 81605 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 33 total
• Cancer dependency (DepMap): dependent in 80.2% of screened cell lines
• MANE Select transcript: NM_030914

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28378
Approved symbol	URM1
Name	ubiquitin related modifier 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC2668
Ensembl gene	ENSG00000167118
Ensembl biotype	protein_coding
OMIM	612693
Entrez	81605

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000372847, ENST00000372850, ENST00000372853, ENST00000470840, ENST00000483206, ENST00000899715, ENST00000928501

RefSeq mRNA: 3 — MANE Select: NM_030914 NM_001135947, NM_001265582, NM_030914

CCDS: CCDS48035, CCDS59148, CCDS6900

Canonical transcript exons

ENST00000372853 — 5 exons

Exon	Start	End
ENSE00001109945	128378036	128378106
ENSE00001611809	128389666	128392016
ENSE00001696807	128371374	128371415
ENSE00003564216	128387816	128387897
ENSE00003639110	128389261	128389309

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 96.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.8175 / max 329.5148, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98755	61.8175	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	96.62	gold quality
apex of heart	UBERON:0002098	95.00	gold quality
parotid gland	UBERON:0001831	94.99	silver quality
mucosa of transverse colon	UBERON:0004991	94.98	gold quality
stromal cell of endometrium	CL:0002255	94.86	gold quality
body of pancreas	UBERON:0001150	94.39	gold quality
monocyte	CL:0000576	94.27	gold quality
mononuclear cell	CL:0000842	94.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.13	gold quality
leukocyte	CL:0000738	93.96	gold quality
right adrenal gland	UBERON:0001233	93.54	gold quality
body of stomach	UBERON:0001161	93.53	gold quality
right adrenal gland cortex	UBERON:0035827	93.36	gold quality
left adrenal gland	UBERON:0001234	93.33	gold quality
heart left ventricle	UBERON:0002084	93.30	gold quality
left adrenal gland cortex	UBERON:0035825	93.25	gold quality
prefrontal cortex	UBERON:0000451	93.22	gold quality
granulocyte	CL:0000094	93.11	gold quality
cardiac ventricle	UBERON:0002082	93.06	gold quality
right atrium auricular region	UBERON:0006631	92.98	gold quality
transverse colon	UBERON:0001157	92.80	gold quality
left coronary artery	UBERON:0001626	92.78	gold quality
gastrocnemius	UBERON:0001388	92.75	gold quality
right frontal lobe	UBERON:0002810	92.72	gold quality
smooth muscle tissue	UBERON:0001135	92.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.67	gold quality
lower esophagus	UBERON:0013473	92.66	gold quality
thoracic aorta	UBERON:0001515	92.57	gold quality
descending thoracic aorta	UBERON:0002345	92.56	gold quality
skin of leg	UBERON:0001511	92.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.00
E-MTAB-6524	no	71.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

109 targeting URM1, 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-9-5P	100.00	72.28	2361
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6752-3P	99.72	66.71	1587

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 80.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• The UBA4-URM1 system represents the evolutionary link between protein conjugation and protein modification by sulfur carrier proteins. (PMID:18491921)
• Urm1 is activated by an unusual mechanism to yield a thiocarboxylate intermediate that serves as sulfur donor in tRNA thiolation reactions (PMID:19017811)
• Urm1 has a conserved dual role by integrating the functions of prokaryotic sulfur carriers with those of eukaryotic protein modifiers of the Ub family (PMID:21209336)
• observations suggest that Urm1 activation is more similar to that of a prokaryotic sulfur carrier protein than that of a ubiquitin-like protein (PMID:21245332)
• ubiquitin-like Urm1.Uba4 systems are conserved and exchangeable between human and yeast cells (PMID:25747390)
• Molecular basis for the bifunctional Uba4-Urm1 sulfur-relay system in tRNA thiolation and ubiquitin-like conjugation. (PMID:32901956)
• The emerging roles of ubiquitin-like protein Urm1 in eukaryotes. (PMID:33548388)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	urm1	ENSDARG00000091198
mus_musculus	Urm1	ENSMUSG00000069020
rattus_norvegicus	Urm1	ENSRNOG00000026636
drosophila_melanogaster	Urm1	FBGN0053276
caenorhabditis_elegans		WBGENE00185048

Protein

Protein identifiers

Ubiquitin-related modifier 1 — Q9BTM9 (reviewed: Q9BTM9)

All UniProt accessions (2): Q9BTM9, Q5T4A9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a sulfur carrier required for 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln). Serves as sulfur donor in tRNA 2-thiolation reaction by being thiocarboxylated (-COSH) at its C-terminus by MOCS3. The sulfur is then transferred to tRNA to form 2-thiolation of mcm(5)S(2)U. Also acts as a ubiquitin-like protein (UBL) that is covalently conjugated via an isopeptide bond to lysine residues of target proteins such as MOCS3, ATPBD3, CTU2, USP15 and CAS. The thiocarboxylated form serves as substrate for conjugation and oxidative stress specifically induces the formation of UBL-protein conjugates.

Subunit / interactions. Component of a complex at least composed of URM1, CTU2/NCS2 and CTU1/ATPBD3.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Post-translational modifications. C-terminal thiocarboxylation occurs in 2 steps, it is first acyl-adenylated (-COAMP) via the hesA/moeB/thiF part of MOCS3, then thiocarboxylated (-COSH) via the rhodanese domain of MOCS3.

Pathway. tRNA modification; 5-methoxycarbonylmethyl-2-thiouridine-tRNA biosynthesis.

Similarity. Belongs to the URM1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BTM9-1	1	yes
Q9BTM9-2	2
Q9BTM9-3	3

RefSeq proteins (3): NP_001129419, NP_001252511, NP_112176* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012675	Beta-grasp_dom_sf	Homologous_superfamily
IPR015221	Urm1	Family
IPR016155	Mopterin_synth/thiamin_S_b	Homologous_superfamily

Pfam: PF09138

UniProt features (9 total): mutagenesis site 3, modified residue 2, splice variant 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTM9-F1	94.60	0.93

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 (3): 101, 101, 101

Mutagenesis-validated functional residues (3):

Position	Phenotype
101	mildly decreases mocs3-dependent amp formation.
101	decreases mocs3-dependent amp formation.
101	abolishes mocs3-dependent amp formation and loss of nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol

MSigDB gene sets: 133 (showing top): MORF_MBD4, CGGAARNGGCNG_UNKNOWN, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_PSMC2, PATIL_LIVER_CANCER, MORF_SKP1A, GOBP_RNA_MODIFICATION, GATA6_01, MORF_PPP6C, MORF_PPP2R4, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GUO_HEX_TARGETS_UP, BENPORATH_NOS_TARGETS, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P

GO Biological Process (4): tRNA wobble uridine modification (GO:0002098), protein urmylation (GO:0032447), tRNA thio-modification (GO:0034227), tRNA processing (GO:0008033)

GO Molecular Function (3): protein tag activity (GO:0031386), sulfur carrier activity (GO:0097163), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tRNA wobble base modification	1
protein modification by small protein conjugation	1
tRNA modification	1
RNA processing	1
tRNA metabolic process	1
molecular tag activity	1
molecular carrier activity	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
URM1	CTU1	Q7Z7A3	996
URM1	MOCS3	O95396	956
URM1	NFS1	Q9Y697	821
URM1	MPST	P25325	816
URM1	UFM1	P61960	802
URM1	CTU2	Q2VPK5	757
URM1	GABARAPL2	P60520	719
URM1	ELP3	Q9H9T3	718
URM1	TRMT112	Q9UI30	717
URM1	TST	Q16762	708
URM1	F5GZY7	F5GZY7	708
URM1	FAU	P35544	706
URM1	MCM5	P33992	691
URM1	KTI12	Q96EK9	681
URM1	NEDD8	Q15843	680

IntAct

26 interactions, top by confidence:

A	B	Type	Score
ACBD6	NMT2	psi-mi:“MI:0914”(association)	0.870
URM1	CTU1	psi-mi:“MI:0915”(physical association)	0.720
URM1	CTU1	psi-mi:“MI:0407”(direct interaction)	0.720
THAP11	HCFC1	psi-mi:“MI:0914”(association)	0.630
URM1	MOCS3	psi-mi:“MI:0195”(covalent binding)	0.590
URM1	MOCS3	psi-mi:“MI:0915”(physical association)	0.590
URM1	USP15	psi-mi:“MI:0915”(physical association)	0.500
URM1	CSE1L	psi-mi:“MI:0915”(physical association)	0.500
URM1	CTU2	psi-mi:“MI:0915”(physical association)	0.400
URM1	VIPR2	psi-mi:“MI:0915”(physical association)	0.370
CTU1	HSPA1B	psi-mi:“MI:0914”(association)	0.350
URM1	OGT	psi-mi:“MI:0914”(association)	0.350
URM1	ELP1	psi-mi:“MI:0914”(association)	0.350
STAC2	EIF1AX	psi-mi:“MI:0914”(association)	0.350
CEP41	ATP12A	psi-mi:“MI:0914”(association)	0.350
AJUBA	DHX16	psi-mi:“MI:0914”(association)	0.350
AKAP7	PRKAR2A	psi-mi:“MI:0914”(association)	0.350
ZDHHC21	SPRYD4	psi-mi:“MI:0914”(association)	0.350
URM1	TOMM40	psi-mi:“MI:0914”(association)	0.350
URM1	flaN	psi-mi:“MI:0915”(physical association)	0.000
ASCC2	URM1	psi-mi:“MI:0915”(physical association)	0.000
URM1	TBL3	psi-mi:“MI:0915”(physical association)	0.000
CDK11B	URM1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): URM1 (Affinity Capture-RNA), URM1 (Affinity Capture-RNA), GDPGP1 (Co-fractionation), URM1 (Affinity Capture-RNA), URM1 (Two-hybrid), URM1 (Reconstituted Complex), URM1 (Affinity Capture-RNA), URM1 (Affinity Capture-MS), URM1 (Affinity Capture-MS), URM1 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), URM1 (Affinity Capture-MS), HIST2H3PS2 (Affinity Capture-MS), URM1 (Affinity Capture-MS), URM1 (Affinity Capture-MS)

ESM2 similar proteins: A0MDQ1, A5DTV4, A6R989, A6S5X1, A6ZVR0, A7ETU4, A7TQ77, A8IC48, A8P008, A9YUB5, B0D4J6, B0W3S2, B2WIC3, B3CKG1, B3H7G2, B3LTL7, B3M611, B3NFA2, B4GUT1, B4HVA2, B4J272, B4KYT0, B4LE67, B4MLV0, B4PCA1, B4QKW3, B5DQK2, B5FVI0, B6SXH2, G0SE11, P0CT26, P40554, Q0D6M1, Q148F0, Q16Y28, Q1E493, Q1HQ10, Q2U9H6, Q54QN0, Q59WK2

Diamond homologs: A0MDQ1, A3GFM6, A5DTV4, A6R989, A6S5X1, A6ZVR0, A7ETU4, A7TQ77, A8IC48, A8P008, A9YUB5, B0D4J6, B0W3S2, B2WIC3, B3CKG1, B3H7G2, B3LTL7, B3M611, B3NFA2, B4GUT1, B4HVA2, B4J272, B4KYT0, B4LE67, B4MLV0, B4PCA1, B4QKW3, B5DQK2, B5FVI0, B6SXH2, G0SE11, P0CT26, P40554, Q0D6M1, Q148F0, Q16Y28, Q1E493, Q1HQ10, Q2U9H6, Q54QN0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

970 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128378020:T:TA	acceptor_gain	1.0000
9:128378103:CCCT:C	donor_gain	1.0000
9:128378103:CCCTG:C	donor_loss	1.0000
9:128378104:CCT:C	donor_gain	1.0000
9:128378105:CTG:C	donor_loss	1.0000
9:128378106:TG:T	donor_loss	1.0000
9:128378107:G:C	donor_loss	1.0000
9:128378107:G:GG	donor_gain	1.0000
9:128378108:T:TC	donor_loss	1.0000
9:128378109:G:GT	donor_loss	1.0000
9:128378110:AGTAT:A	donor_loss	1.0000
9:128387804:A:AG	acceptor_gain	1.0000
9:128387805:T:G	acceptor_gain	1.0000
9:128387810:TTCCA:T	acceptor_loss	1.0000
9:128387811:TCCA:T	acceptor_loss	1.0000
9:128387812:CCAG:C	acceptor_loss	1.0000
9:128387813:CA:C	acceptor_loss	1.0000
9:128387814:A:AG	acceptor_gain	1.0000
9:128387814:A:AT	acceptor_loss	1.0000
9:128387814:AG:A	acceptor_gain	1.0000
9:128387814:AGG:A	acceptor_gain	1.0000
9:128387814:AGGG:A	acceptor_gain	1.0000
9:128387815:G:A	acceptor_gain	1.0000
9:128387815:G:GT	acceptor_gain	1.0000
9:128387815:GGG:G	acceptor_gain	1.0000
9:128387815:GGGG:G	acceptor_gain	1.0000
9:128387815:GGGGA:G	acceptor_gain	1.0000
9:128387887:G:GT	donor_gain	1.0000
9:128387894:GCGT:G	donor_gain	1.0000
9:128387895:CGTG:C	donor_loss	1.0000

AlphaMissense

648 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:128389281:T:C	L70P	0.997
9:128389275:T:C	L68P	0.995
9:128389298:T:A	W76R	0.995
9:128389298:T:C	W76R	0.995
9:128389709:T:C	F94S	0.995
9:128389723:C:G	H99D	0.995
9:128387831:T:C	L41P	0.994
9:128389269:G:A	G66E	0.994
9:128389287:A:T	N72I	0.994
9:128389305:T:C	L78P	0.994
9:128389723:C:A	H99N	0.994
9:128389727:G:A	G100D	0.994
9:128387879:T:C	F57S	0.993
9:128389268:G:A	G66R	0.993
9:128389268:G:C	G66R	0.993
9:128389275:T:A	L68Q	0.992
9:128389295:G:C	D75H	0.992
9:128389725:C:A	H99Q	0.992
9:128389725:C:G	H99Q	0.992
9:128389703:T:A	V92D	0.991
9:128389714:T:C	S96P	0.991
9:128389721:T:C	L98P	0.991
9:128389278:T:A	V69E	0.990
9:128389297:C:A	D75E	0.990
9:128389297:C:G	D75E	0.990
9:128389726:G:C	G100R	0.990
9:128389263:G:C	R64P	0.989
9:128389721:T:A	L98Q	0.989
9:128389269:G:T	G66V	0.988
9:128389292:G:C	A74P	0.988

dbSNP variants (sampled 300 via entrez): RS1000044256 (9:128387142 T>C), RS1000322117 (9:128385551 T>A,C,G), RS1000499153 (9:128372917 A>C,G,T), RS1000581783 (9:128370440 C>G,T), RS1000635785 (9:128370067 G>A), RS1000842238 (9:128376163 C>G), RS1000900145 (9:128382763 A>G), RS1001045466 (9:128379528 G>A,T), RS1001192432 (9:128391110 A>G), RS1001588782 (9:128371743 T>G), RS1001641142 (9:128371554 G>A,C), RS1001895090 (9:128371735 C>A,T), RS1002228401 (9:128378818 G>A), RS1002248499 (9:128377587 T>C), RS1002286144 (9:128373671 C>T)

Disease associations

OMIM: gene MIM:612693 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
ICG 001	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	decreases expression	1
Ivermectin	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases expression	1
Vanadates	decreases expression	1

Clinical trials (associated diseases)

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