TYW2

Summary

TYW2 (tRNA wybutosine-synthesizing protein 2, HGNC:26091) is a protein-coding gene on chromosome 8q24.13, encoding tRNA wybutosine-synthesizing protein 2 homolog (Q53H54). S-adenosyl-L-methionine-dependent transferase that acts as a component of the wybutosine biosynthesis pathway.

Wybutosine (yW) is a hypermodified guanosine at the 3-prime position adjacent to the anticodon of phenylalanine tRNA that stabilizes codon-anticodon interactions during decoding on the ribosome. TRMT12 is the human homolog of a yeast gene essential for yW synthesis (Noma and Suzuki, 2006).

Source: NCBI Gene 55039 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 49 total
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_017956

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26091
Approved symbol	TYW2
Name	tRNA wybutosine-synthesizing protein 2
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20772, Trm12, TYW2
Ensembl gene	ENSG00000183665
Ensembl biotype	protein_coding
OMIM	611244
Entrez	55039

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000328599, ENST00000521443, ENST00000522518

RefSeq mRNA: 1 — MANE Select: NM_017956 NM_017956

CCDS: CCDS6349

Canonical transcript exons

ENST00000328599 — 1 exons

Exon	Start	End
ENSE00001330290	124450820	124453026

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 91.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.3019 / max 97.5973, expressed in 1671 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90499	5.9766	1652
90500	0.3253	159

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	91.70	silver quality
endothelial cell	CL:0000115	89.68	gold quality
male germ cell	CL:0000015	88.11	silver quality
choroid plexus epithelium	UBERON:0003911	87.98	gold quality
monocyte	CL:0000576	82.62	gold quality
islet of Langerhans	UBERON:0000006	82.59	gold quality
calcaneal tendon	UBERON:0003701	82.59	gold quality
mononuclear cell	CL:0000842	82.48	gold quality
leukocyte	CL:0000738	82.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.13	gold quality
gastrocnemius	UBERON:0001388	81.23	gold quality
muscle of leg	UBERON:0001383	81.10	gold quality
secondary oocyte	CL:0000655	80.62	gold quality
amniotic fluid	UBERON:0000173	79.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.20	gold quality
mucosa of transverse colon	UBERON:0004991	78.71	gold quality
cortical plate	UBERON:0005343	78.50	gold quality
stromal cell of endometrium	CL:0002255	78.23	gold quality
granulocyte	CL:0000094	78.08	gold quality
parotid gland	UBERON:0001831	77.80	silver quality
tendon	UBERON:0000043	77.73	gold quality
cranial nerve II	UBERON:0000941	77.67	gold quality
prefrontal cortex	UBERON:0000451	77.28	gold quality
rectum	UBERON:0001052	77.18	gold quality
muscle organ	UBERON:0001630	77.08	gold quality
tibialis anterior	UBERON:0001385	77.04	silver quality
right adrenal gland cortex	UBERON:0035827	76.65	gold quality
left adrenal gland cortex	UBERON:0035825	76.60	gold quality
right adrenal gland	UBERON:0001233	76.56	gold quality
left adrenal gland	UBERON:0001234	76.52	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting TYW2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-6794-3P	98.76	66.99	894
HSA-MIR-6830-3P	98.62	68.07	1760

Literature-anchored findings (GeneRIF, showing 2)

• analysis by RT-qPCR using RNA from 30 breast tumors showed TRMT12 was overexpressed >2 fold in 87% of the tumors. TRMT12 is a homologue of a yeast gene encoding a tRNA methyltransferase involved in the posttranscriptional modification of tRNA(Phe) (PMID:17440925)
• Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. (PMID:32778592)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trmt12	ENSDARG00000060338
mus_musculus	Trmt12	ENSMUSG00000037085
rattus_norvegicus	Trmt12	ENSRNOG00000008978
caenorhabditis_elegans		WBGENE00009586

Paralogs (2): TRMT5 (ENSG00000126814), TYW3 (ENSG00000162623)

Protein

Protein identifiers

tRNA wybutosine-synthesizing protein 2 homolog — Q53H54 (reviewed: Q53H54)

Alternative names: tRNA(Phe) (4-demethylwyosine(37)-C(7)) aminocarboxypropyltransferase

All UniProt accessions (2): E5RHH6, Q53H54

UniProt curated annotations — full annotation on UniProt →

Function. S-adenosyl-L-methionine-dependent transferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3’-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the transfer of the alpha-amino-alpha-carboxypropyl (acp) group from S-adenosyl-L-methionine to the C-7 position of 4-demethylwyosine (imG-14) to produce wybutosine-86.

Pathway. tRNA modification; wybutosine-tRNA(Phe) biosynthesis.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM5/TYW2 family.

RefSeq proteins (1): NP_060426* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR030382	MeTrfase_TRM5/TYW2	Domain
IPR056743	TRM5-TYW2-like_MTfase	Domain
IPR056744	TRM5/TYW2-like_N	Domain
IPR056745	TYW2_N	Domain

Pfam: PF02475, PF25132, PF25133

Enzyme classification (BRENDA):

• EC 2.5.1.114 — tRNAPhe (4-demethylwyosine37-C7) aminocarboxypropyltransferase (BRENDA: 4 organisms, 2 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• 4-demethylwyosine(37) in tRNA(Phe) + S-adenosyl-L-methionine = 4-demethyl-7-[(3S)-3-amino-3-carboxypropyl]wyosine(37) in tRNA(Phe) + S-methyl-5’-thioadenosine + H(+) (RHEA:36355)

UniProt features (12 total): mutagenesis site 5, binding site 4, chain 1, sequence conflict 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53H54-F1	85.13	0.73

Functional residue map

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

Ligand- & substrate-binding residues (4): 218; 225; 265; 293–294

Mutagenesis-validated functional residues (5):

Position	Phenotype
293	does not affect activity.
225	lack of activity.
242	does not affect activity.
248	does not affect activity.
265	lack of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782861	Synthesis of wybutosine at G37 of tRNA(Phe)

MSigDB gene sets: 112 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_TRNA_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_RNA_METHYLATION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_RNA_MODIFICATION, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_TRNA_METHYLATION, GOBP_METHYLATION, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, GOBP_GLYCOSYL_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA

GO Biological Process (4): tRNA methylation (GO:0030488), wybutosine biosynthetic process (GO:0031591), tRNA modification (GO:0006400), tRNA processing (GO:0008033)

GO Molecular Function (4): tRNA methyltransferase activity (GO:0008175), tRNA 4-demethylwyosine alpha-amino-alpha-carboxypropyltransferase activity (GO:0102522), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA modification in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA modification	2
catalytic activity, acting on a tRNA	2
RNA methylation	1
glycosyl compound biosynthetic process	1
tRNA processing	1
RNA modification	1
RNA processing	1
tRNA metabolic process	1
RNA methyltransferase activity	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

951 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TYW2	TYW3	Q6IPR3	916
TYW2	LCMT2	O60294	902
TYW2	TYW1	Q9NV66	871
TYW2	TRMT5	Q32P41	845
TYW2	BUD23	O43709	730
TYW2	TSR3	Q9UJK0	710
TYW2	TRMT10A	Q8TBZ6	649
TYW2	METTL5	Q9NRN9	641
TYW2	TYW5	A2RUC4	600
TYW2	FTSJ1	Q9UET6	578
TYW2	CTU1	Q7Z7A3	575
TYW2	ELP3	Q9H9T3	557
TYW2	TRMT9B	Q9P272	550
TYW2	TRMT11	Q7Z4G4	545
TYW2	TRMT2A	Q8IZ69	526

IntAct

15 interactions, top by confidence:

A	B	Type	Score
TRMT12	LNX1	psi-mi:“MI:0915”(physical association)	0.560
LNX1	TRMT12	psi-mi:“MI:0915”(physical association)	0.560
TRMT12	PRDM6	psi-mi:“MI:0915”(physical association)	0.560
NUDT1	TRMT12	psi-mi:“MI:0915”(physical association)	0.560
ZNF556	LRP4	psi-mi:“MI:0914”(association)	0.530
TRMT12	HSPA8	psi-mi:“MI:0914”(association)	0.530
CKAP2	WDR46	psi-mi:“MI:0914”(association)	0.350
TRMT12	PRDM6	psi-mi:“MI:0915”(physical association)	0.000
NUDT1	TRMT12	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): LNX1 (Two-hybrid), TRMT12 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), HSPA4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), TRMT12 (Two-hybrid), TRMT12 (Two-hybrid), HSPA4 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), TRMT12 (Affinity Capture-MS), TRMT12 (Affinity Capture-MS), WDR45B (Co-fractionation), CA5B (Co-fractionation), TRMT12 (Proximity Label-MS)

ESM2 similar proteins: A1A4L5, A8N339, A8WHT1, A9T6G5, B6DMK2, C0NUP2, C5XX79, C8VJ35, D0NLC2, E3KWE1, E3WPP8, F4HQE2, F4NUJ6, F5HAU9, F6HH45, F6VSS6, F7A355, F7GSQ4, P38793, Q0P466, Q16VC0, Q32P41, Q3MHN8, Q4KLT3, Q4R3U8, Q4V8B8, Q4WX30, Q53H54, Q58D65, Q5KBP2, Q6KAI0, Q6NTR1, Q7Q5Z3, Q7TS68, Q80Y20, Q84MA1, Q8BG71, Q8BYH3, Q8GYE8, Q8H4D4

Diamond homologs: A0CC46, A2E5K9, A4HWT0, A8B4Q0, A8N339, A8WHT1, A9T6G5, B3L2G0, B5DPF1, B7FTW3, B8A5G9, B8BQY5, C0H537, C0NUP2, C4M572, C4YH95, C5XX79, C7YK87, C8VJ35, D0NLC2, D3BT31, E3KWE1, E3WPP8, F4NUJ6, F5HAU9, F6H2F8, F6HH45, F6VSS6, F7A355, F7GSQ4, P38793, Q16VC0, Q32P41, Q3MHN8, Q4CNL4, Q4DPN8, Q4MYY2, Q4PHW2, Q4QEY9, Q4R3U8

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — SACA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

103 predictions. Top by Δscore:

Variant	Effect	Δscore
8:124451584:T:TA	acceptor_gain	0.9400
8:124451355:T:A	acceptor_gain	0.9200
8:124451354:CTG:C	acceptor_gain	0.6900
8:124451585:G:A	acceptor_gain	0.6700
8:124452441:ATT:A	acceptor_gain	0.6600
8:124450928:A:AG	donor_gain	0.5700
8:124451352:T:A	acceptor_gain	0.5200
8:124451373:A:AC	acceptor_gain	0.4800
8:124451356:G:GC	acceptor_gain	0.4400
8:124452443:TGATA:T	acceptor_gain	0.4300
8:124452444:GATAA:G	acceptor_gain	0.4300
8:124451956:AG:A	acceptor_gain	0.4000
8:124451957:GG:G	acceptor_gain	0.4000
8:124452443:T:A	acceptor_gain	0.3700
8:124451956:A:AG	acceptor_gain	0.3600
8:124451957:G:GG	acceptor_gain	0.3600
8:124452442:T:G	acceptor_gain	0.3600
8:124451253:TTGAG:T	donor_loss	0.3500
8:124451254:TGAGG:T	donor_loss	0.3500
8:124451256:AGGT:A	donor_loss	0.3500
8:124451257:GG:G	donor_loss	0.3500
8:124451258:GT:G	donor_loss	0.3500
8:124451259:T:A	donor_loss	0.3500
8:124451144:GAGC:G	donor_gain	0.3400
8:124451260:G:GG	donor_loss	0.3400
8:124451592:T:G	acceptor_gain	0.3400
8:124451261:AGTCG:A	donor_loss	0.3300
8:124451262:G:C	donor_loss	0.3200
8:124451337:AT:A	acceptor_gain	0.3200
8:124452441:A:AG	acceptor_gain	0.3200

AlphaMissense

2897 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:124451879:T:A	W318R	0.989
8:124451879:T:C	W318R	0.989
8:124451590:C:A	N221K	0.979
8:124451590:C:G	N221K	0.979
8:124452243:T:C	L439P	0.978
8:124451889:C:A	A321D	0.972
8:124452237:T:C	L437P	0.972
8:124451576:T:C	F217L	0.960
8:124451578:C:A	F217L	0.960
8:124451578:C:G	F217L	0.960
8:124451384:T:A	W153R	0.959
8:124451384:T:C	W153R	0.959
8:124451598:A:T	E224V	0.958
8:124451607:G:C	R227P	0.956
8:124451669:T:C	F248L	0.953
8:124451671:T:A	F248L	0.953
8:124451671:T:G	F248L	0.953
8:124451933:C:G	H336D	0.953
8:124451599:G:C	E224D	0.952
8:124451599:G:T	E224D	0.952
8:124451346:T:C	L140P	0.951
8:124451901:T:C	L325S	0.951
8:124452170:T:A	W415R	0.951
8:124452170:T:C	W415R	0.951
8:124451664:G:A	G246D	0.950
8:124451715:C:A	A263D	0.950
8:124451835:C:A	A303E	0.950
8:124451925:T:C	L333S	0.950
8:124451602:G:C	K225N	0.949
8:124451602:G:T	K225N	0.949

dbSNP variants (sampled 300 via entrez): RS1001576778 (8:124450915 T>TA), RS1003833508 (8:124452471 G>T), RS1003940180 (8:124449085 G>A,C), RS1004029774 (8:124449899 T>A,C), RS1007673667 (8:124453188 C>G,T), RS1007722099 (8:124452478 C>G,T), RS1008346436 (8:124450034 G>A), RS1009655422 (8:124453028 A>G), RS1012553291 (8:124452419 C>G), RS1012607864 (8:124452056 A>G), RS1012680917 (8:124453505 G>A,C), RS1012733097 (8:124453053 T>C), RS1013289236 (8:124449365 G>A,C), RS1014486085 (8:124449438 G>C), RS1015059432 (8:124451238 C>T)

Disease associations

OMIM: gene MIM:611244 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
sodium arsenite	decreases expression	1
cylindrospermopsin	increases expression	1
bisphenol S	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Gasoline	decreases expression, increases abundance, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	decreases expression, increases abundance, affects cotreatment	1
Smoke	decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases expression	1
Vitamin E	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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