YTHDC2

Summary

YTHDC2 (YTH N6-methyladenosine RNA binding protein C2, HGNC:24721) is a protein-coding gene on chromosome 5q22.2, encoding 3’-5’ RNA helicase YTHDC2 (Q9H6S0). 3’-5’ RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells.

This gene encodes a member of the DEAH (Asp-Glu-Ala-His) subfamily of proteins, part of the DEAD (Asp-Glu-Ala-Asp) box family of RNA helicases. The encoded protein binds to N6-methyladenosine, a common modified RNA nucleotide that is enriched in the stop codons and 3’ UTRs of eukaryotic messenger RNAs. Binding of proteins to this modified nucleotide may regulate mRNA translation and stability. This gene may be associated with susceptibility to pancreatic cancer in human patients, and knockdown of this gene resulted in reduced proliferation in a human liver cancer cell line.

Source: NCBI Gene 64848 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 237 total
• MANE Select transcript: NM_022828

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24721
Approved symbol	YTHDC2
Name	YTH N6-methyladenosine RNA binding protein C2
Location	5q22.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ2194, FLJ10053, DKFZp564A186
Ensembl gene	ENSG00000047188
Ensembl biotype	protein_coding
OMIM	616530
Entrez	64848

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000161863, ENST00000503857, ENST00000506333, ENST00000507567, ENST00000512600, ENST00000514720, ENST00000515883, ENST00000873029, ENST00000935141, ENST00000935142, ENST00000935143, ENST00000948227, ENST00000948228, ENST00000948229, ENST00000948230, ENST00000948231

RefSeq mRNA: 3 — MANE Select: NM_022828 NM_001345975, NM_001345976, NM_022828

CCDS: CCDS4113

Canonical transcript exons

ENST00000161863 — 30 exons

Exon	Start	End
ENSE00000364322	113581417	113581709
ENSE00000588976	113563859	113564131
ENSE00000760310	113563373	113563492
ENSE00000760317	113565893	113566019
ENSE00000760320	113579586	113579695
ENSE00000760321	113584302	113584479
ENSE00000760323	113591996	113592178
ENSE00000890208	113593303	113593390
ENSE00000890209	113593482	113595284
ENSE00001180473	113524981	113525177
ENSE00001180477	113515272	113515362
ENSE00001306353	113526586	113526785
ENSE00001326602	113561080	113561185
ENSE00002072379	113513694	113514082
ENSE00003472462	113539074	113539181
ENSE00003526046	113540968	113541116
ENSE00003555670	113553942	113554022
ENSE00003574653	113548955	113549020
ENSE00003588202	113534305	113534407
ENSE00003593810	113556052	113556134
ENSE00003597552	113553767	113553854
ENSE00003605547	113532879	113533045
ENSE00003615764	113535642	113535798
ENSE00003625127	113553181	113553359
ENSE00003663061	113567092	113567297
ENSE00003665275	113591041	113591244
ENSE00003667967	113542368	113542503
ENSE00003674510	113548541	113548667
ENSE00003677774	113567654	113567849
ENSE00003693892	113553590	113553686

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 92.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0156 / max 182.7587, expressed in 1813 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58020	21.9377	1806
58022	0.7679	224
58024	0.6702	324
58021	0.3842	155
58023	0.2556	90

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	92.58	gold quality
blood vessel layer	UBERON:0004797	92.10	gold quality
upper leg skin	UBERON:0004262	91.58	gold quality
skin of hip	UBERON:0001554	91.54	gold quality
hair follicle	UBERON:0002073	91.49	gold quality
tibia	UBERON:0000979	91.27	gold quality
calcaneal tendon	UBERON:0003701	91.22	gold quality
choroid plexus epithelium	UBERON:0003911	91.07	gold quality
epithelium of nasopharynx	UBERON:0001951	90.75	gold quality
nasopharynx	UBERON:0001728	90.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.70	gold quality
germinal epithelium of ovary	UBERON:0001304	90.53	gold quality
visceral pleura	UBERON:0002401	90.43	gold quality
palpebral conjunctiva	UBERON:0001812	90.02	gold quality
superficial temporal artery	UBERON:0001614	90.00	gold quality
parietal pleura	UBERON:0002400	89.96	gold quality
pleura	UBERON:0000977	89.80	gold quality
tonsil	UBERON:0002372	89.39	gold quality
sural nerve	UBERON:0015488	89.15	gold quality
eye	UBERON:0000970	89.06	gold quality
esophagus squamous epithelium	UBERON:0006920	88.46	gold quality
gingival epithelium	UBERON:0001949	88.21	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.13	gold quality
left ovary	UBERON:0002119	88.11	gold quality
jejunal mucosa	UBERON:0000399	88.07	gold quality
oral cavity	UBERON:0000167	88.02	gold quality
mucosa of stomach	UBERON:0001199	87.98	gold quality
urethra	UBERON:0000057	87.95	gold quality
secondary oocyte	CL:0000655	87.82	gold quality
endometrium	UBERON:0001295	87.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, IL1B, TNF

miRNA regulators (miRDB)

104 targeting YTHDC2, 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-4262	100.00	73.26	3931
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
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-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1250-3P	99.96	70.04	4038

Literature-anchored findings (GeneRIF, showing 26)

• CAHL is a CsA associated helicase-like protein, which would form trimer complex with cyclophilin B and NS5B of HCV. (PMID:21559518)
• data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2 (PMID:24269672)
• Our results suggest that the YTHDC2 gene could be a potential candidate for pancreatic cancer susceptibility and a useful marker for early detection (PMID:24834797)
• binding affinities of the YTH domains of three human proteins and yeast YTH domain protein Pho92 (PMID:26318451)
• Suggest that RNA helicase YTHDC2 contributes to colon adenocarcinoma metastasis by promoting translation of HIF-1alpha. (PMID:26996300)
• YTHDC2 was recently found to promote a “fast-track” expression program for specific mRNAs, and our data suggest that YTHDC2 accomplishes this by recruitment of the RNA degradation machinery to regulate the stability of m(6)A-containing mRNAs and by utilizing its distinct RNA-binding domains to bridge interactions between m(6)A-containing mRNAs and the ribosomes to facilitate their efficient translation. (PMID:29970596)
• The (6)-methyladenosine (m(6)A) binding pocket is conserved in YTH domain of ATP-dependent RNA helicase YTHDC2 (YTHDC2). (PMID:31472957)
• m(6) A RNA methylation regulators contribute to malignant progression in rectal cancer. (PMID:32043594)
• Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population. (PMID:32047883)
• N(6) -Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes. (PMID:32150756)
• N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition. (PMID:33649237)
• N6-methyladenosine reader YTHDC2 and eraser FTO may determine hepatocellular carcinoma prognoses after transarterial chemoembolization. (PMID:33713148)
• Targeting SLC3A2 subunit of system XC(-) is essential for m(6)A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma. (PMID:33785413)
• [LIM-domain binding protein 2 regulated by m(6)A modification inhibits lung adenocarcinoma cell proliferation in vitro]. (PMID:33849822)
• [Role of m (6)A Reader YTHDC2 in Differentiation of Human Bone Marrow Mesenchymal Stem Cells]. (PMID:34018357)
• Downregulation of m(6)A Reader YTHDC2 Promotes the Proliferation and Migration of Malignant Lung Cells via CYLD/NF-kappaB Pathway. (PMID:34326699)
• Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency. (PMID:35138268)
• The m(6)A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay. (PMID:35177478)
• Construction and clinical evaluation of N6-methyladenosine risk signature of YTHDC2, IGF2BP2, and HNRNPC in head and neck squamous cell carcinoma. (PMID:36416324)
• lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m[6]A reader YTHDC2. (PMID:36581942)
• Overexpression of YTHDC2 contributes to the progression of prostate cancer and predicts poor outcomes in patients with prostate cancer. (PMID:36644951)
• YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling. (PMID:37162682)
• Crosstalk between RNA m[6]A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells. (PMID:37474847)
• The m6A Reader YTHDC2 Suppresses Lung Adenocarcinoma Tumorigenesis by Destabilizing MRPL12. (PMID:38129673)
• The m[6]A reader YTHDC2 regulates UVB-induced DNA damage repair and histone modification. (PMID:38190286)
• A homozygous missense variant in YTHDC2 induces azoospermia in two siblings. (PMID:39223386)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ythdc2	ENSDARG00000103525
mus_musculus	Ythdc2	ENSMUSG00000034653
rattus_norvegicus	Ythdc2	ENSRNOG00000039241
drosophila_melanogaster	CG8915	FBGN0030833

Paralogs (18): DHX33 (ENSG00000005100), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), DHX15 (ENSG00000109606), HELB (ENSG00000127311), DHX30 (ENSG00000132153), DHX34 (ENSG00000134815), DHX9 (ENSG00000135829), DHX38 (ENSG00000140829), DQX1 (ENSG00000144045), DHX37 (ENSG00000150990), TDRD9 (ENSG00000156414), DHX57 (ENSG00000163214), DHX36 (ENSG00000174953), DHX16 (ENSG00000204560)

Protein

Protein identifiers

3’-5’ RNA helicase YTHDC2 — Q9H6S0 (reviewed: Q9H6S0)

Alternative names: YTH domain-containing protein 2

All UniProt accessions (4): Q9H6S0, D6R9T8, D6RA70, D6RF50

UniProt curated annotations — full annotation on UniProt →

Function. 3’-5’ RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells. Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, a modification present at internal sites of mRNAs and some non-coding RNAs that plays a role in the efficiency of RNA processing and stability. Essential for ensuring a successful progression of the meiotic program in the germline by regulating the level of m6A-containing RNAs. Acts by binding and promoting degradation of m6A-containing mRNAs: the 3’-5’ RNA helicase activity is required for this process and RNA degradation may be mediated by XRN1 exoribonuclease. Required for both spermatogenesis and oogenesis.

Subunit / interactions. Interacts with MEIOC; binds transcripts that regulate the mitotic cell cycle inhibiting progression into metaphase, thereby allowing meiotic prophase to proceed normally. Interacts (via ANK repeats) with XRN1. Interacts with ZCCHC4. Associates with the small ribosomal subunit. Interacts with RBM46.

Subcellular location. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed in testis. Not detected in spermatogonia next to the tubule wall but is strongly expressed in spermatocytes, suggesting that it is up-regulated in germ cells upon entry into meiosis.

Domain organisation. The YTH domain mediates RNA-binding. It recognizes and binds N6-methyladenosine (m6A)-containing RNAs.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily.

RefSeq proteins (3): NP_001332904, NP_001332905, NP_073739* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001374	R3H_dom	Domain
IPR001650	Helicase_C-like	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR007275	YTH_domain	Domain
IPR007502	Helicase-assoc_dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR011709	DEAD-box_helicase_OB_fold	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR034083	R3H_DEXH_helicase	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR036867	R3H_dom_sf	Homologous_superfamily
IPR048333	HA2_WH	Domain
IPR059023	RNA_hel_CTD	Domain

Pfam: PF00270, PF00271, PF01424, PF04146, PF04408, PF07717, PF21010, PF26026

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (47 total): strand 8, modified residue 7, helix 6, compositionally biased region 5, domain 4, binding site 4, sequence conflict 3, sequence variant 2, mutagenesis site 2, repeat 2, region of interest 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9SZP	X-RAY DIFFRACTION	1.58
6K6U	X-RAY DIFFRACTION	2.27
9H36	X-RAY DIFFRACTION	2.62
9H35	X-RAY DIFFRACTION	2.68
2YU6	SOLUTION NMR
6LR2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6S0-F1	77.53	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.

Ligand- & substrate-binding residues (4): 216–223; 1294–1296; 1310; 1360

Post-translational modifications (7): 1089, 1090, 1092, 1202, 1263, 1267, 1281

Mutagenesis-validated functional residues (2):

Position	Phenotype
317	abolished 3’-5’ rna helicase activity.
1360	abolished ability to bind n6-methyladenosine (m6a)-containing rnas.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 184 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, ATF_B, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_OOGENESIS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_MEIOTIC_CELL_CYCLE, BILD_SRC_ONCOGENIC_SIGNATURE, GOBP_HOST_MEDIATED_PERTURBATION_OF_VIRAL_PROCESS, CREB_Q4, GOBP_POSITIVE_REGULATION_OF_MEIOTIC_CELL_CYCLE, CADWELL_ATG16L1_TARGETS_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE

GO Biological Process (10): spermatid development (GO:0007286), response to tumor necrosis factor (GO:0034612), host-mediated activation of viral genome replication (GO:0044829), oocyte development (GO:0048599), meiotic cell cycle (GO:0051321), germline cell cycle switching, mitotic to meiotic cell cycle (GO:0051729), response to interleukin-1 (GO:0070555), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), oogenesis (GO:0048477)

GO Molecular Function (13): RNA binding (GO:0003723), helicase activity (GO:0004386), ATP binding (GO:0005524), ATP-dependent activity, acting on RNA (GO:0008186), ATP hydrolysis activity (GO:0016887), 3’-5’ RNA helicase activity (GO:0034458), RNA polymerase binding (GO:0070063), N6-methyladenosine-containing RNA reader activity (GO:1990247), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), RNA helicase activity (GO:0003724), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), ribonucleoprotein granule (GO:0035770), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
germ cell development	3
ATP-dependent activity	3
cellular anatomical structure	3
response to cytokine	2
binding	2
cytoplasm	2
spermatid differentiation	1
host-mediated activation of viral process	1
host-mediated perturbation of viral genome replication	1
oocyte differentiation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
cell cycle switching, mitotic to meiotic cell cycle	1
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
female gamete generation	1
nucleic acid binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
RNA helicase activity	1
enzyme binding	1
RNA binding	1
protein-RNA adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
catalytic activity	1
nuclear lumen	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
supramolecular complex	1

Protein interactions and networks

STRING

3671 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YTHDC2	XRN1	Q8IZH2	984
YTHDC2	MEIOC	A2RUB1	963
YTHDC2	METTL3	Q86U44	942
YTHDC2	ALKBH5	Q6P6C2	918
YTHDC2	METTL14	Q9HCE5	918
YTHDC2	WTAP	Q15007	917
YTHDC2	VIRMA	Q69YN4	910
YTHDC2	ZC3H13	Q5T200	896
YTHDC2	RBM15	Q96T37	889
YTHDC2	HNRNPC	P07910	877
YTHDC2	RBMX	P38159	865
YTHDC2	HNRNPA2B1	P22626	864
YTHDC2	IGF2BP1	Q9NZI8	860
YTHDC2	IGF2BP2	Q9Y6M1	853
YTHDC2	FTO	Q9C0B1	850

IntAct

244 interactions, top by confidence:

A	B	Type	Score
TEN1	CTC1	psi-mi:“MI:0914”(association)	0.860
LARP7	CCNT1	psi-mi:“MI:0914”(association)	0.850
NOP53	RRP8	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
RPL7A	NOP56	psi-mi:“MI:0914”(association)	0.640
FGF3	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNF512	ZNF724	psi-mi:“MI:0914”(association)	0.530
RPL18A	RRP8	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
ZBTB38	IPO7	psi-mi:“MI:0914”(association)	0.530
ZSCAN31	DHX57	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
RRP8	MAGEB2	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
RPL7L1	ZBTB24	psi-mi:“MI:0914”(association)	0.530
RPL19	ZBTB24	psi-mi:“MI:0914”(association)	0.530
RPL13A	NVL	psi-mi:“MI:0914”(association)	0.530
CBX6	ZBTB24	psi-mi:“MI:0914”(association)	0.530
PRR3	MRPS14	psi-mi:“MI:0914”(association)	0.530

BioGRID (260): YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Co-fractionation), YTHDC2 (Affinity Capture-MS), YTHDC2 (Biochemical Activity), YTHDC2 (Proximity Label-MS), YTHDC2 (Proximity Label-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8J1M587, A3KMI0, A6ZL17, A8WS58, B0W9F4, B2RR83, B3LN76, B3MMA5, B3MSG8, B3NSW1, B4GS98, B4GU19, B4I0K4, B4JNS2, B4L1Z2, B4M891, B4M9A8, B4MX21, B4NDG5, B4PZB4, B5VE38, O18017, P32863, P38086, P41410, Q0PCS3, Q16X92, Q19546, Q21489, Q29FS3, Q29KH2, Q3YK19, Q5D892, Q5R746, Q5SXJ3, Q6P158, Q6P5D3, Q7QEI1, Q7Z478, Q93575

Diamond homologs: A0A9P4XWM4, A9LNK9, B2RR83, E7F1H9, G4MRQ6, P59326, Q0VCZ3, Q3MK94, Q4R5D9, Q5R746, Q5RFL8, Q7Z739, Q8BYK6, Q91YT7, Q9BYJ9, Q9H6S0, Q9VBZ5, Q9Y5A9, A3KMI0, B0XDC4, B3M383, B3P3W1, B4GEU5, B4HLH4, B4JT42, B4K5R2, B4LX81, B4NBB0, B4PRJ9, B8A4F4, D4A2Z8, F4HYJ7, F4I9Q5, F4IDQ6, F4IJV4, F4ILR7, F4IM84, F4INY4, F4JMJ3, F4KGU4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF2	“up-regulates quantity by expression”	YTHDC2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 220 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
Peptide chain elongation	24	22.4×	3e-24
Viral mRNA Translation	24	22.4×	3e-24
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	24	22.1×	3e-24
Selenocysteine synthesis	24	21.2×	7e-24
Eukaryotic Translation Termination	24	21.2×	7e-24
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	24	20.8×	9e-24
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	24	20.8×	9e-24
Formation of a pool of free 40S subunits	24	19.8×	3e-23

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	25	23.6×	8e-25
ribosomal large subunit biogenesis	8	18.1×	2e-06
translation	27	14.2×	8e-21
ribosomal small subunit biogenesis	12	13.9×	1e-08
rRNA processing	16	11.6×	2e-10
negative regulation of translation	11	11.0×	1e-06
regulation of alternative mRNA splicing, via spliceosome	8	10.0×	2e-04
RNA processing	8	8.9×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	152
Likely benign	22
Benign	29

Top pathogenic / likely-pathogenic (0)

SpliceAI

5203 predictions. Top by Δscore:

Variant	Effect	Δscore
5:113514078:GAGAG:G	donor_gain	1.0000
5:113514080:GAG:G	donor_gain	1.0000
5:113514081:AGGT:A	donor_loss	1.0000
5:113514083:GTGAG:G	donor_loss	1.0000
5:113514084:T:A	donor_loss	1.0000
5:113515359:AAGG:A	donor_gain	1.0000
5:113515361:GG:G	donor_gain	1.0000
5:113515362:GG:G	donor_gain	1.0000
5:113526576:A:AG	acceptor_gain	1.0000
5:113526582:A:AG	acceptor_gain	1.0000
5:113526583:A:G	acceptor_gain	1.0000
5:113526708:G:GT	donor_gain	1.0000
5:113532874:TTCA:T	acceptor_loss	1.0000
5:113532877:A:AG	acceptor_gain	1.0000
5:113532878:G:A	acceptor_loss	1.0000
5:113532878:G:GG	acceptor_gain	1.0000
5:113533042:GCAG:G	donor_gain	1.0000
5:113533043:CAGG:C	donor_loss	1.0000
5:113533046:GT:G	donor_loss	1.0000
5:113533047:T:A	donor_loss	1.0000
5:113542362:TTGTA:T	acceptor_loss	1.0000
5:113542363:TGTA:T	acceptor_loss	1.0000
5:113542364:GTAG:G	acceptor_loss	1.0000
5:113542365:TAGAC:T	acceptor_loss	1.0000
5:113542366:A:AG	acceptor_gain	1.0000
5:113542366:A:C	acceptor_loss	1.0000
5:113542367:G:GC	acceptor_loss	1.0000
5:113542367:G:GG	acceptor_gain	1.0000
5:113542367:GA:G	acceptor_gain	1.0000
5:113542367:GACT:G	acceptor_gain	1.0000

AlphaMissense

9425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:113515309:A:C	R75S	1.000
5:113515309:A:T	R75S	1.000
5:113515319:C:G	H79D	1.000
5:113532928:G:C	R242P	1.000
5:113532972:G:C	A257P	1.000
5:113532973:C:A	A257D	1.000
5:113532982:T:A	V260D	1.000
5:113532984:G:C	A261P	1.000
5:113532985:C:A	A261D	1.000
5:113532995:A:C	R264S	1.000
5:113532995:A:T	R264S	1.000
5:113533009:G:A	G269D	1.000
5:113533020:G:C	G273R	1.000
5:113533021:G:A	G273D	1.000
5:113533021:G:T	G273V	1.000
5:113553599:T:C	L626P	1.000
5:113553969:A:C	S694R	1.000
5:113553971:C:A	S694R	1.000
5:113553971:C:G	S694R	1.000
5:113553997:T:A	V703D	1.000
5:113556097:T:A	W727R	1.000
5:113556097:T:C	W727R	1.000
5:113556125:G:C	R736P	1.000
5:113563901:G:A	G829R	1.000
5:113563901:G:C	G829R	1.000
5:113563901:G:T	G829W	1.000
5:113563902:G:A	G829E	1.000
5:113566008:T:A	L944H	1.000
5:113566008:T:C	L944P	1.000
5:113567098:T:A	V950D	1.000

dbSNP variants (sampled 300 via entrez): RS1000009974 (5:113591728 A>G,T), RS1000058056 (5:113583673 G>A), RS1000068100 (5:113514241 G>C), RS1000100343 (5:113514516 A>C,G,T), RS1000115797 (5:113537232 T>A), RS1000167171 (5:113551170 A>T), RS1000216983 (5:113589136 AT>A), RS1000295800 (5:113519048 T>C,G), RS1000344618 (5:113539295 A>G), RS1000345624 (5:113575167 T>A), RS1000345782 (5:113521512 C>A,T), RS1000362377 (5:113557061 AAT>A), RS1000419170 (5:113575440 G>A,T), RS1000467613 (5:113550213 T>G), RS1000471331 (5:113549562 A>G)

Disease associations

OMIM: gene MIM:616530 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000982_8	F-cell distribution in sickle cell anaemia	8.000000e-06
GCST006867_45	Type 2 diabetes	5.000000e-08
GCST009391_868	Metabolite levels	2.000000e-06
GCST010796_1048	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_1049	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST012484_13	Cerebral amyloid angiopathy x APOEe4 status interaction in Alzheimer’s disease	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004576	fetal hemoglobin measurement
EFO:0010535	sucrose measurement
EFO:0004327	electrocardiography
EFO:0007659	APOE carrier status

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Plant Extracts	affects cotreatment, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cadmium sulfate	increases abundance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Cidofovir	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Demecolcine	decreases expression	1
Clodronic Acid	affects expression	1
Drugs, Chinese Herbal	increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8AH	Abcam Raji YTHDC2 KO	Cancer cell line	Male
CVCL_C0BC	Abcam THP-1 YTHDC2 KO	Cancer cell line	Male
CVCL_C7CZ	Abcam PC-3 YTHDC2 KO	Cancer cell line	Male
CVCL_F1R6	HyCyte KGN KO-hYTHDC2	Cancer cell line	Female
CVCL_XV18	HAP1 YTHDC2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer