Affinage

YTHDC2

3'-5' RNA helicase YTHDC2 · UniProt Q9H6S0

Length
1430 aa
Mass
160.2 kDa
Annotated
2026-06-11
67 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YTHDC2 is a multidomain cytoplasmic RNA helicase and m6A reader that governs post-transcriptional control of gene expression, with its central physiological role being the orchestration of the mitosis-to-meiosis transition and meiotic progression in germ cells (PMID:28809393, PMID:29087293, PMID:35305312). It recognizes m6A through a YTH domain bearing a conserved hydrophobic binding pocket, while its R3H domain contributes additional cellular RNA binding (PMID:28809393, PMID:29970596). The protein possesses RNA-induced, ATP-dependent 3'→5' helicase activity, and recruits the 5'→3' exoribonuclease XRN1 through ankyrin repeats inserted between its RecA helicase modules, an interaction that enhances its intrinsically weak unwinding activity and couples target engagement to mRNA decay (PMID:29033321, PMID:35305312). Notably, in vivo germline function depends on the helicase/ATPase activity rather than on m6A recognition: catalytic-dead helicase mutants are infertile in a dominant-negative manner while m6A-pocket mutants remain fertile, and germline YTHDC2 binds U-rich and UG-rich motifs in 3'UTRs and coding sequences rather than m6A sites (PMID:35305312, PMID:35058317). YTHDC2 acts together with MEIOC (and RBM46) as RNA-granule-associated partners; its loss causes germ cells to retain mitotic regulators such as Cyclin A2 and fail meiosis, and conditional ablation reveals a second requirement for progression through meiotic prophase to diplotene (PMID:29087293, PMID:29360036, PMID:39378093, PMID:42249589). In somatic and disease contexts YTHDC2 reads m6A to either destabilize transcripts via XRN1-coupled decay or to enhance translation by unwinding 5'-UTR and CDS secondary structures, including a role in resolving CDS structure to promote translation elongation (PMID:29033321, PMID:31767846, PMID:26996300), and it terminates antiviral innate immunity by recruiting the exonuclease ISG20 to degrade m6A-modified IFN-β mRNA (PMID:37776518). Human pathogenic variants in YTHDC2 cause primary ovarian insufficiency and non-obstructive azoospermia, the latter recapitulated in a knock-in mouse and accompanied by reduced MEIOC/RBM46 and aberrant mitotic cell-cycle gene expression (PMID:35138268, PMID:42249589).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2017 High

    Established YTHDC2 as an m6A reader required for spermatogenesis, linking m6A recognition to both translational enhancement and reduced mRNA abundance of targets.

    Evidence m6A binding assays, translational efficiency and mRNA abundance measurements, Ythdc2 knockout mice with germ cell arrest

    PMID:28809393

    Open questions at the time
    • Did not separate m6A-reading from helicase activity as the basis of the fertility phenotype
    • Direct enzymatic activity not yet reconstituted
  2. 2017 High

    Defined the enzymatic and decay-coupling machinery of YTHDC2, showing it is an ATP-dependent 3'→5' helicase that recruits XRN1 to degrade germline transcripts.

    Evidence In vitro ATPase/helicase reconstitution, domain mapping of the ankyrin-XRN1 interaction, m6A transcriptome mapping in testes

    PMID:29033321

    Open questions at the time
    • Quantitative contribution of XRN1 to in vivo target decay not established
    • Relationship between helicase activity and m6A reading unresolved
  3. 2017 High

    Showed YTHDC2 enforces a clean mitosis-to-meiosis switch by clearing mitotic regulators, defining its developmental function.

    Evidence Knockout mouse, immunofluorescence for meiotic markers, RNA binding and co-IP with RNA granule components

    PMID:29087293

    Open questions at the time
    • Whether Ccna2 clearance is direct via decay versus indirect not fully resolved
    • RNA granule partner identities only partially defined
  4. 2018 High

    Dissected domain contributions, localizing m6A reading to the YTH pocket, RNA binding to YTH+R3H, and XRN1 binding to ankyrin repeats, and placed YTHDC2 at the ribosome mRNA entry/exit channel.

    Evidence Domain deletion analysis, RNA binding assays, CRAC, ribosomal subunit co-IP

    PMID:29970596

    Open questions at the time
    • Functional consequence of small-subunit association not mechanistically tied to translation outcomes
    • Single-lab structural inference
  5. 2018 High

    A missense (ketu) allele and MEIOC epistasis established YTHDC2 as a cytoplasmic helicase acting with MEIOC, with evolutionary conservation across metazoans.

    Evidence ENU mutagenesis screen, missense knock-in mouse, in vitro helicase assay, genetic epistasis with MEIOC, phylogenetics

    PMID:29360036

    Open questions at the time
    • Molecular nature of the MEIOC-YTHDC2 functional partnership not defined
    • Mechanism of premature metaphase entry unresolved
  6. 2019 High

    Connected YTHDC2 helicase function to translation elongation, showing it resolves CDS secondary structure marked by m6A.

    Evidence Ribosome profiling, RNA structure analysis, knockdown with translational efficiency and reporter assays

    PMID:31767846

    Open questions at the time
    • Direct demonstration that YTHDC2 unwinds CDS structure in vitro not shown here
    • Single-lab
  7. 2019 High

    Provided structural basis for m6A recognition, defining the YTH domain pocket shared in architecture with other YTH readers.

    Evidence X-ray crystallography of the human YTHDC2 YTH domain

    PMID:31472957

    Open questions at the time
    • Structure of full-length protein or helicase domain not determined
    • No RNA-bound complex structure
  8. 2020 Medium

    Refined the YTH domain solution architecture, showing distinct β4-β5 loop features versus YTHDC1 that shape its m6A pocket.

    Evidence NMR resonance assignment and solution topology

    PMID:32930954

    Open questions at the time
    • No functional mutagenesis validation in this study
    • Selectivity consequences of loop differences not tested
  9. 2021 Medium

    Showed YTHDC2 can both destabilize and translationally activate distinct m6A targets in somatic cancer contexts, broadening its post-transcriptional repertoire.

    Evidence RIP, mRNA stability and polysome/luciferase assays, YTH mutants, xenograft/PDX models across SLC7A11, IGF1R, YAP

    PMID:32850334 PMID:33232910 PMID:34911015

    Open questions at the time
    • Determinants selecting decay versus translation outcomes unknown
    • Generalizability beyond individual cancer lines unclear
  10. 2021 High

    Demonstrated a pachytene-stage requirement and confirmed YTHDC2 primarily targets transcripts for degradation, with germline dysregulation uncorrelated to m6A status.

    Evidence Conditional knockout, single-cell transcriptomics, CLIP-seq, microtubule inhibitor rescue

    PMID:34910909

    Open questions at the time
    • Mechanism linking transcript clearance to telomere clustering not defined
    • Why m6A status fails to predict targets unresolved at this stage
  11. 2021 High

    Implicated YTHDC2 in viral RNA translation, showing helicase activity supports HCV IRES-dependent initiation at an m6A site.

    Evidence m6A site mutagenesis, IRES luciferase reporters, helicase-dead E332Q mutant

    PMID:33649237

    Open questions at the time
    • Role of host cofactors beyond La antigen not mapped
    • Single-lab
  12. 2022 High

    Resolved the central mechanistic question by showing helicase/ATPase activity, not m6A reading, is essential for fertility, with germline binding to U-rich/UG-rich rather than m6A motifs.

    Evidence YTH-pocket vs ATPase knock-in mice, in vitro helicase reconstitution with XRN1, CLIP-seq, single-cell transcriptomics, zebrafish; corroborated by independent knock-in study

    PMID:35058317 PMID:35305312

    Open questions at the time
    • How sequence specificity (U-rich) is encoded without m6A reading unresolved
    • Dominant-negative mechanism of catalytic-dead mutant not structurally explained
  13. 2022 Medium

    Extended YTHDC2's m6A-reader role to immune and viral transcript protection, showing it stabilizes m6A-modified IL-6 mRNA against SOX-induced decay during KSHV infection.

    Evidence m6A mapping, RIP, m6A mutant reporters, knockdown during KSHV lytic infection

    PMID:35177478

    Open questions at the time
    • Mechanism of protection versus its decay-promoting activity unresolved
    • Single-lab
  14. 2022 Medium

    Linked YTHDC2 to human reproductive disease, associating pathogenic helicase-region variants with primary ovarian insufficiency.

    Evidence Whole-exome sequencing, structural modeling, human fetal ovary expression

    PMID:35138268

    Open questions at the time
    • Functional reconstitution of variant effects limited
    • Causality not tested in an animal model in this study
  15. 2023 High

    Defined an innate-immune termination function, showing YTHDC2 recruits ISG20 to degrade m6A-modified IFN-β mRNA late in infection.

    Evidence Enzymolysis-based RNA pull-down, KO mouse, RIP for ISG20 interaction, in vitro and in vivo viral infection

    PMID:37776518

    Open questions at the time
    • Structural basis of ISG20 recruitment versus XRN1 recruitment unknown
    • Whether helicase activity is required for IFN-β degradation not dissected
  16. 2024 High

    Identified a second, post-meiotic-prophase requirement for YTHDC2 and reinforced its collaboration with RNA-granule RNA-binding proteins including MEIOC.

    Evidence Inducible conditional knockout, immunofluorescence for meiotic markers, co-IP for RNA-binding partners

    PMID:39378093

    Open questions at the time
    • Distinct molecular targets at the pachytene-to-diplotene step not enumerated
    • Granule composition only partially defined
  17. 2024 Medium

    Expanded m6A-dependent target regulation to neural, retinal, and metabolic contexts, showing tissue-specific translational enhancement and decay of distinct mRNAs.

    Evidence Conditional KO (rod-specific), RIP, polysome profiling, m6A-IP, mRNA stability assays across Lrp2, Ppef2/Pde6b, and somatic targets

    PMID:35716070 PMID:36574062 PMID:38157933 PMID:38334797 PMID:38432455 PMID:38465865

    Open questions at the time
    • Several individual-target studies are low-confidence single-lab RIP-based claims
    • Whether helicase activity drives these outcomes generally untested
  18. 2026 High

    Confirmed YTHDC2 as a human azoospermia gene and mechanistically tied disease variants to loss of MEIOC/RBM46 and failed mitotic-gene clearance.

    Evidence Patient whole-exome sequencing, CRISPR knock-in mouse recapitulating arrest, marker immunofluorescence, qRT-PCR, western blotting

    PMID:42249589

    Open questions at the time
    • Direct biochemical effect of each variant on helicase activity not measured
    • How partner loss is mechanistically caused by variants unresolved
  19. 2025 Medium

    Demonstrated pharmacological tractability of the YTH m6A pocket with a selective small-molecule inhibitor that reduces target mRNA expression.

    Evidence Deep-learning drug design, in vitro IC50, cellular target engagement and selectivity profiling

    PMID:41495018

    Open questions at the time
    • Inhibitor targets m6A pocket, which is dispensable for germline function, limiting relevance to that role
    • In vivo efficacy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How YTHDC2 achieves m6A-independent U-rich/UG-rich target selectivity in germ cells, and what distinguishes its decay-promoting versus translation-enhancing outcomes on different transcripts, remains unresolved.
  • No structure of the full-length helicase bound to RNA
  • Determinants choosing XRN1-coupled decay versus structure-resolving translational activation unknown
  • Mechanism integrating helicase activity with RNA-granule partners not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140098 catalytic activity, acting on RNA 4 GO:0045182 translation regulator activity 3 GO:0140657 ATP-dependent activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 1 GO:0005840 ribosome 1
Pathway
R-HSA-1474165 Reproduction 5 R-HSA-8953854 Metabolism of RNA 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
ISG20MEIOCRBM46XRN1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 YTHDC2 selectively binds m6A at its consensus motif via its YTH domain, enhances the translation efficiency of its target mRNAs, and decreases their mRNA abundance. Ythdc2 knockout mice are infertile, with germ cells failing to progress past the zygotene stage, establishing its critical role in spermatogenesis. m6A binding assays, knockout mouse model, translational efficiency assays, mRNA abundance measurements Cell research High 28809393
2017 YTHDC2 is an RNA-induced ATPase with 3'→5' RNA helicase activity in vitro. It recruits the 5'→3' exoribonuclease XRN1 via Ankyrin repeats inserted between the RecA modules of the RNA helicase domain. Loss of YTHDC2 causes upregulation of m6A-enriched transcripts in testes, indicating a role in degrading m6A-modified germline transcripts. In vitro ATPase and helicase assays, biochemical interaction studies (ankyrin repeat-XRN1 interaction), high-throughput m6A transcriptome mapping, mutant testes expression analysis Molecular cell High 29033321
2017 YTHDC2 facilitates a clean switch from mitosis to meiosis in mouse germ cells. YTHDC2-deficient male germ cells maintain expression of Cyclin A2 and fail to properly express meiotic markers, attempting an abnormal mitotic-like division instead of continuing through meiotic prophase. YTHDC2 binds multiple transcripts including Ccna2 and interacts with RNA granule components. Knockout mouse model, immunofluorescence, RNA binding assays, co-immunoprecipitation with RNA granule components eLife High 29087293
2018 The YTH domain of YTHDC2 preferentially binds m6A-containing RNAs via a conserved hydrophobic pocket. The ankyrin repeats mediate an RNA-independent interaction with XRN1. Both the YTH and R3H domains contribute to cellular RNA binding. YTHDC2 interacts with the small ribosomal subunit in close proximity to the mRNA entry/exit sites, as shown by CRAC (crosslinking and analysis of cDNA). Domain deletion analysis, RNA binding assays, CRAC (crosslinking and analysis of cDNA), co-immunoprecipitation with ribosomal subunits RNA (New York, N.Y.) High 29970596
2018 A missense mutation in Ythdc2 (ketu allele) causes sterility in mice, with mutant germ cells entering meiosis but proceeding prematurely to aberrant metaphase and apoptosis. YTHDC2 is cytoplasmic and has 3'→5' RNA helicase activity in vitro. YTHDC2 partners with MEIOC, and ketu phenocopies MEIOC mutants. YTHDC2 orthologs are present throughout metazoans; Bgcn in Drosophilidae is descended from a Ythdc2 gene duplication. ENU mutagenesis screen, missense mutant mouse model, in vitro helicase assay, subcellular fractionation/immunofluorescence for cytoplasmic localization, genetic epistasis with MEIOC mutants eLife High 29360036
2019 CDS-localized m6A positively regulates translation elongation by resolving mRNA secondary structures; this elongation-promoting effect requires the RNA helicase-containing m6A reader YTHDC2. CDS m6A leads to ribosome pausing in a codon-specific manner, but removing CDS m6A decreases translation further. Ribosome profiling, RNA structure analysis, YTHDC2 knockdown with translational efficiency measurements, luciferase reporter assays Nature communications High 31767846
2019 Crystal structure of the human YTHDC2 YTH domain was determined. It adopts similar architecture to other YTH domain structures, contains a conserved m6A binding pocket, and shares an RNA binding surface with YTHDC1. X-ray crystallography Biochemical and biophysical research communications High 31472957
2020 NMR resonance assignment of the YTHDC2 YTH domain revealed a β1-α1-β2-α2-β3-β4-β5-α3-β6-α4 topology. Unlike YTHDC1, the m6A-binding pocket of YTHDC2 formed by the β4-β5 loop is stabilized by electrostatic interaction, and the β4-β5 loops of YTHDC1 and YTHDC2 differ in length and amino acid composition. NMR spectroscopy (1H, 13C, 15N resonance assignment), solution structure determination Biomolecular NMR assignments Medium 32930954
2021 YTHDC2, via its m6A-recognizing YTH domain, binds m6A-modified SLC7A11 mRNA and promotes its decay (mRNA destabilization), thereby suppressing SLC7A11-dependent cystine uptake and antioxidant function in lung adenocarcinoma cells. RIP assay, mRNA stability assays, m6A-dependent RNA binding validation, YTH domain mutant analysis, mouse xenograft/PDX models Redox biology Medium 33232910
2021 YTHDC2 promotes translation initiation of IGF1R mRNA by binding to it, activating the IGF1R/AKT/S6 signaling pathway and conferring radiotherapy resistance in nasopharyngeal carcinoma cells. YTHDC2 knockdown/overexpression, RIP assay demonstrating physical binding to IGF1R mRNA, luciferase reporter for translation initiation, in vitro and in vivo radioresistance assays Frontiers in oncology Medium 32850334
2021 YTHDC2 deficiency causes microtubule-dependent telomere clustering and apoptosis at the pachytene stage. YTHDC2-bound mRNAs are enriched in upregulated genes in mutant germ cells (including microtubule network protein transcripts), indicating YTHDC2 primarily targets mRNAs for degradation. Dysregulation of transcripts in YTHDC2-deficient pachytene cells does not correlate with m6A status. Conditional knockout mouse model, single-cell transcriptomics, CLIP-seq for YTHDC2 binding sites, microtubule inhibitor rescue experiments Cell reports High 34910909
2021 YTHDC2 recognizes m6A-methylated adenosine at nucleotide 331 of the HCV IRES element (in concert with the cellular La antigen) and supports HCV IRES-dependent translation initiation. A helicase-dead YTHDC2 (E332Q) mutant failed to stimulate HCV IRES translation initiation. m6A consensus motif mutagenesis, luciferase reporter assays for IRES-mediated translation, helicase-dead mutant (E332Q) functional analysis, RNA-protein interaction assays Proceedings of the National Academy of Sciences of the United States of America High 33649237
2022 The 3'→5' RNA helicase activity of YTHDC2 (not its m6A-binding YTH domain) is essential for mouse fertility. YTH domain point mutant mice are fertile, but catalytic-dead helicase mutations cause infertility in a dominant-negative manner. XRN1 interaction enhances the weak intrinsic helicase activity of YTHDC2. YTHDC2 binds U-rich motifs in 3' UTRs of mouse testicular RNA targets (not m6A sites). Ythdc2 mutant zebrafish are also infertile, demonstrating conserved function. YTH domain point mutant knock-in mice (fertile), ATPase catalytic-dead mutant knock-in mice (infertile, dominant negative), in vitro helicase reconstitution with/without XRN1, CLIP-seq for binding site identification, single-cell transcriptomics, zebrafish mutant model Molecular cell High 35305312
2022 Mutation of the m6A-binding pocket of YTHDC2 has no detectable effect on gametogenesis or mouse fertility. CLIP data defined YTHDC2-binding sites as U-rich and UG-rich motif-containing regions in 3' UTRs and coding sequences, distinct from m6A sites during spermatogenesis. Mutation of the ATPase motif does not affect meiotic entry but blocks meiotic prophase I progression, causing sterility. m6A-binding pocket mutant knock-in mice, ATPase motif mutant knock-in mice, CLIP-seq for binding site mapping, whole-testis ribosome profiling Genes & development High 35058317
2022 During KSHV lytic infection, YTHDC2 is recruited to m6A-modified IL-6 mRNA (within its SOX resistance element in the 3' UTR) and is necessary for protection of the IL-6 transcript from SOX-induced decay. m6A mapping during KSHV infection, YTHDC2 knockdown, RIP assay for YTHDC2 binding to IL-6 mRNA, m6A mutant reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 35177478
2022 Pathogenic variants in YTHDC2 (p.P856R in the HA2 helicase-associated domain; p.E377* truncating the helicase core) are associated with primary ovarian insufficiency (POI) in women. The p.P856R variant results in a less flexible protein that disrupts downstream conformational kinetics of the HA2 domain. YTHDC2 is expressed in the developing human fetal ovary and upregulated in meiotic germ cells. Whole-exome sequencing, protein structural modeling, expression analysis in human fetal ovary, functional domain mapping JCI insight Medium 35138268
2013 YTHDC2 (previously known as CAHL) forms a trimer complex with cyclophilin B and NS5B of hepatitis C virus and facilitates HCV genome replication. The CRE site in the YTHDC2 promoter is critical for its transcription; c-Jun and ATF-2 bind to this CRE site, and TNF-α induces their biological activity. HDAC activity is required for efficient YTHDC2 expression. Co-immunoprecipitation for trimer complex, chromatin immunoprecipitation (ChIP) for transcription factor binding, siRNA knockdown, HDAC inhibitor (TSA) treatment, luciferase promoter assays Gene Medium 24269672
2016 YTHDC2 promotes translation initiation by unwinding the 5' UTR of HIF-1α mRNA, enhancing HIF-1α protein expression. Knockdown of YTHDC2 reduced HIF-1α protein levels and inhibited metastasis of colon tumor cells in vitro and in vivo. A luciferase reporter containing the 5' UTR of HIF-1α mRNA showed reduced activity in YTHDC2-silenced cells. siRNA knockdown, luciferase reporter with HIF-1α 5'UTR, metastasis assays in vitro and in vivo, western blotting Cancer letters Medium 26996300
2021 YTHDC2 promotes translation efficiency of YAP mRNA in gastric cancer cells by recognizing m6A-modified YAP mRNA at the 5'-UTR, enhancing YAP translation without affecting mRNA levels. YAP/TEAD in turn directly targets the YTHDC2 promoter to activate its transcription, forming a positive regulatory loop. RIP assay, m6A methylation assay, polysome profiling for translational efficiency, CRISPR-KO, ChIP for YAP/TEAD binding at YTHDC2 promoter, luciferase reporter Translational oncology Medium 34911015
2023 YTHDC2 recognizes and binds m6A-modified LIMK1 mRNA; downregulation of YTHDC2 in colorectal cancer cells reduces binding to the m6A site 'GGACA' in LIMK1 mRNA, increasing LIMK1 mRNA stability and expression, which promotes eIF2α phosphorylation, ER stress, and stress granule formation, leading to 5-FU resistance. RIP assay, mRNA stability assay, m6A-IP, YTHDC2 knockdown/overexpression, eIF2α phosphorylation assays, stress granule imaging Cancer letters Medium 37778684
2023 YTHDC2 induces termination of antiviral innate immune response at the late stage of virus infection by recruiting the IFN-stimulated exonuclease ISG20 to degrade m6A-modified IFN-β mRNA. YTHDC2 is induced in macrophages at the late stage of virus infection. In vitro and in vivo YTHDC2 deficiency increases IFN-β production. Enzymolysis-based RNA pull-down (eRP) to identify YTHDC2 as IFN-β mRNA-binding protein, YTHDC2 KO mouse model, RIP assay for ISG20 interaction, in vitro and in vivo viral infection models Cell reports High 37776518
2024 YTHDC2 recognizes and binds m6A-modified Ppef2 mRNA (at coding sequence) and Pde6b mRNA (at 5'-UTR) via its YTH domain, enhancing their translation efficiency without affecting mRNA levels. Rod-specific Ythdc2 knockout mice show diminished scotopic ERG responses and progressive retinal degeneration, with decreased PPEF2 and PDE6B protein levels. Rod-specific conditional KO mouse, ERG recordings, RIP assay, m6A-IP, polysome profiling, multi-omics analysis Journal of genetics and genomics Medium 38157933
2022 METTL3-mediated m6A modification of Lrp2 mRNA enhances its stability and translation efficiency via the reader protein Ythdc2, promoting neurogenesis in neural stem cells. Depletion of Ythdc2 in this context abrogates the Mettl3-dependent promotion of Lrp2 expression and neuronal differentiation. siRNA knockdown of Mettl3/Mettl14/Ythdc2, m6A-IP for Lrp2, RIP for Ythdc2 binding to Lrp2 mRNA, mRNA stability assays, translation efficiency assays in neural stem cells FASEB journal Medium 35716070
2024 YTHDC2 has a second essential role in late spermatocytes beyond the mitosis-to-meiosis transition. Conditional knockout of Ythdc2 after meiotic prophase initiation allowed cells to reach pachytene but blocked transition to diplotene, causing cell death. YTHDC2 co-immunoprecipitates with several RNA-binding proteins (including MEIOC) that localize to RNA granules, suggesting YTHDC2 collaborates with RNA granule components at multiple meiotic stages. Conditional (inducible) knockout mouse model, immunofluorescence for meiotic markers, co-immunoprecipitation for RNA-binding protein interactions Proceedings of the National Academy of Sciences of the United States of America High 39378093
2024 METTL16-mediated m6A modification of SCD1 mRNA increases its RNA decay via the m6A reader YTHDC2 in papillary thyroid carcinoma cells, thereby reducing SCD1-driven lipid metabolism. m6A-IP, RIP assay for YTHDC2 binding to SCD1 mRNA, mRNA stability assay, METTL16 overexpression/knockout Cellular and molecular life sciences : CMLS Low 38334797
2024 YTHDC2 destabilizes NCOA4 mRNA in an m6A-dependent manner (METTL3-dependent m6A modification required), reducing ferritinophagy and alleviating secondary injury after intracerebral hemorrhage. RIP-qPCR confirmed direct YTHDC2 binding to NCOA4 mRNA. RIP-qPCR for YTHDC2-NCOA4 mRNA binding, mRNA stability assay, METTL3 silencing, overexpression in ICH rat model Epigenetics Low 38465865
2024 YTHDC2 mediates METTL3-dependent m6A recognition on AMIGO2 mRNA 5'UTR; METTL3 knockdown decreases m6A modification of AMIGO2 mRNA, diminishing its interaction with YTHDC2 and reducing AMIGO2 expression in RA fibroblast-like synoviocytes. RIP assay for YTHDC2-AMIGO2 mRNA interaction, MeRIP for m6A level on AMIGO2, siRNA knockdown of METTL3/YTHDC2, AMIGO2 overexpression rescue Biochimica et biophysica acta. Molecular basis of disease Low 38432455
2024 YTHDC2 overexpression decreases KDM5B mRNA stability in an m6A-dependent manner in Schwann cells, promoting SIRT3 expression and improving mitochondrial metabolic reprogramming in diabetic peripheral neuropathy. RIP, RNA pull-down, and dual-luciferase reporter assays confirmed YTHDC2-KDM5B mRNA binding. RIP assay, RNA pull-down, dual-luciferase reporter assay, mRNA stability assay, me-RIP for KDM5B m6A levels, XF96 metabolic flux analysis Acta diabetologica Low 36574062
2025 YTHDC2 binds to m6A-modified sites (at nucleotides A1223 and A2824) within the mRNA of the copper transporter SLC31A1 in an m6A-dependent manner, enhancing SLC31A1 mRNA stability and protein expression, thereby increasing intracellular copper transport and inducing cuproptosis to overcome osimertinib resistance. m6A site mutagenesis, RIP assay, mRNA stability assay, YTHDC2 KO/OE in cell lines and PDX models, cuproptosis assays Oncogene Medium 41402633
2026 Biallelic pathogenic missense variants in YTHDC2 (including p.E1164V, p.R880H, p.D382G, p.R98G) cause non-obstructive azoospermia in humans by disrupting the mitotic-to-meiotic transition. A knock-in mouse model carrying the p.E1164V equivalent recapitulates meiotic prophase arrest. Mechanistically, MEIOC and RBM46 (YTHDC2-interacting proteins) are significantly decreased, and mitotic cell cycle regulators (CCNA2, CCND1, WEE1) are aberrantly upregulated in meiosis-marker-expressing cells. Whole-exome sequencing of patient cohort, CRISPR/Cas9 knock-in mouse model, spermatocyte spreading, immunofluorescence for meiotic/mitotic markers, quantitative RT-PCR, western blotting Human reproduction (Oxford, England) High 42249589
2026 YTHDC2 binds RBMS1 mRNA transcripts (shown by RIP) and promotes their degradation, reducing RBMS1 mRNA stability. In ulcerative colitis, decreased YTHDC2 enhances RBMS1 mRNA stability, promoting ferroptosis and inflammation in colonic epithelial cells. RNA immunoprecipitation (RIP), mRNA stability assay, YTHDC2 overexpression/knockdown, DSS colitis mouse model, in vitro LPS model Inflammation Low 41811549
2025 A potent small-molecule inhibitor DC2-C1 (IC50 0.168 μM) was developed targeting the YTHDC2 YTH domain (m6A recognition pocket). In cellular assays, DC2-C1 effectively targets YTHDC2 and reduces expression of multiple YTHDC2 target mRNAs, demonstrating pharmacological tractability of the m6A-binding pocket. Deep learning-based drug discovery (EPMolGen), in vitro binding/inhibition assays (IC50 measurement), cellular target engagement assays, selectivity profiling over other YTH proteins Nature communications Medium 41495018

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell research 867 28809393
2017 Regulation of m6A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Molecular cell 403 29033321
2019 m6A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2. Nature communications 331 31767846
2016 RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer letters 216 26996300
2018 The m6A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1. RNA (New York, N.Y.) 212 29970596
2020 The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox biology 197 33232910
2017 The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. eLife 183 29087293
2021 Targeting SLC3A2 subunit of system XC- is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma. Free radical biology & medicine 152 33785413
2018 ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2. eLife 134 29360036
2022 lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2. Molecular cancer 80 36581942
2020 m6A Reader YTHDC2 Promotes Radiotherapy Resistance of Nasopharyngeal Carcinoma via Activating IGF1R/AKT/S6 Signaling Axis. Frontiers in oncology 71 32850334
2022 The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition. Molecular cell 69 35305312
2021 N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition. Proceedings of the National Academy of Sciences of the United States of America 56 33649237
2021 The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation. Translational oncology 51 34911015
2013 Transcriptional machinery of TNF-α-inducible YTH domain containing 2 (YTHDC2) gene. Gene 44 24269672
2022 YTHDC2 control of gametogenesis requires helicase activity but not m6A binding. Genes & development 40 35058317
2021 Downregulation of m6A Reader YTHDC2 Promotes the Proliferation and Migration of Malignant Lung Cells via CYLD/NF-κB Pathway. International journal of biological sciences 40 34326699
2014 Germline copy number variation in the YTHDC2 gene: does it have a role in finding a novel potential molecular target involved in pancreatic adenocarcinoma susceptibility? Expert opinion on therapeutic targets 40 24834797
2023 LIMK1 m6A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation. Cancer letters 38 37778684
2021 YTHDC2 is essential for pachytene progression and prevents aberrant microtubule-driven telomere clustering in male meiosis. Cell reports 38 34910909
2024 METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism. Cellular and molecular life sciences : CMLS 36 38334797
2022 The m6A reader YTHDC2 is essential for escape from KSHV SOX-induced RNA decay. Proceedings of the National Academy of Sciences of the United States of America 35 35177478
2019 Crystal structure of human YTHDC2 YTH domain. Biochemical and biophysical research communications 33 31472957
2022 Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency. JCI insight 28 35138268
2021 N6-methyladenosine reader YTHDC2 and eraser FTO may determine hepatocellular carcinoma prognoses after transarterial chemoembolization. Archives of toxicology 27 33713148
2024 The biological function of the N6-Methyladenosine reader YTHDC2 and its role in diseases. Journal of translational medicine 25 38790013
2021 YTHDC2-Mediated circYTHDC2 N6-Methyladenosine Modification Promotes Vascular Smooth Muscle Cells Dysfunction Through Inhibiting Ten-Eleven Translocation 2. Frontiers in cardiovascular medicine 25 34660707
2022 Mettl3-mediated m6 A modification of Lrp2 facilitates neurogenesis through Ythdc2 and elicits antidepressant-like effects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 35716070
2021 Protective role of m6A binding protein YTHDC2 on CCNB2 in manganese-induced spermatogenesis dysfunction. Chemico-biological interactions 22 34822792
2020 Critical roles of mRNA m6A modification and YTHDC2 expression for meiotic initiation and progression in female germ cells. Gene 21 32470506
2024 The m6A reader YTHDC2 promotes the pathophysiology of temporal lobe epilepsy by modulating SLC7A11-dependent glutamate dysregulation in astrocytes. Theranostics 18 39310099
2024 m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage. Epigenetics 15 38465865
2023 Enzymolysis-based RNA pull-down identifies YTHDC2 as an inhibitor of antiviral innate response. Cell reports 14 37776518
2022 The m6A reader YTHDC2 promotes SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in diabetic peripheral neuropathy. Acta diabetologica 14 36574062
2024 METTL3 knockdown suppresses RA-FLS activation through m6A-YTHDC2-mediated regulation of AMIGO2. Biochimica et biophysica acta. Molecular basis of disease 13 38432455
2023 YTHDC2-mediated m6A mRNA modification of Id3 suppresses cisplatin resistance in non-small cell lung cancer. Journal of thoracic disease 13 37065597
2023 YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling. Applied biochemistry and biotechnology 13 37162682
2022 YTHDC2 Promotes Malignant Phenotypes of Breast Cancer Cells. Journal of oncology 12 36245989
2023 YTHDC2 inhibits rat bone mesenchymal stem cells osteogenic differentiation by accelerating RUNX2 mRNA degradation via m6A methylation. Heliyon 10 37636387
2023 The m6A Reader YTHDC2 Suppresses Lung Adenocarcinoma Tumorigenesis by Destabilizing MRPL12. Molecular biotechnology 10 38129673
2024 Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection. Journal of medical virology 9 38344929
2024 The m6A reader YTHDC2 regulates UVB-induced DNA damage repair and histone modification. Photochemistry and photobiology 8 38190286
2024 YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 8 39378093
2024 A novel signature constructed by cuproptosis-related RNA methylation regulators suggesting downregulation of YTHDC2 may induce cuproptosis resistance in colorectal cancer. International immunopharmacology 6 39029230
2021 [Role of m 6A Reader YTHDC2 in Differentiation of Human Bone Marrow Mesenchymal Stem Cells]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 6 34018357
2025 The m6A reader YTHDC2 restrains endometrial cancer progression through suppressing hedgehog signaling pathway. Pathology, research and practice 4 40054161
2025 Baicalin targets YTHDC2 and alleviates male reproductive toxicity caused by co-exposure to nanoplastics and manganese through m6A-dependent pathway. Journal of nanobiotechnology 4 40533738
2024 YTHDC2 mediated RNA m6A modification contributes to PM2.5-induced hepatic steatosis. Journal of hazardous materials 4 38943883
2023 The m6A reader YTHDC2 maintains visual function and retinal photoreceptor survival through modulating translation of PPEF2 and PDE6B. Journal of genetics and genomics = Yi chuan xue bao 4 38157933
2025 YTHDC2 manipulates anti-tumoral macrophage polarization and predicts favorable outcomes in triple negative breast cancer. NPJ precision oncology 2 40274959
2025 METTL3-Driven m6A Epigenetic Remodeling of lncRNA-AU020206 Stabilizes SLC7A11 via YTHDC2 Attenuates Apoptosis and Ferroptosis in Cerebral Ischemia/Reperfusion Injury. Biomolecules 2 41154582
2026 Deep learning-assisted discovery of a potent and cell-active inhibitor of RNA N6-methyladenosine recognition protein YTHDC2. Nature communications 1 41495018
2025 Identification and functional regulation of three alternative splicing isoforms of the Ythdc2 gene in Miichthysmiiuy. Developmental and comparative immunology 1 40049308
2025 YTHDC2 promotes sepsis-induced cardiomyopathy by activating apoptosis and NF-κB pathway. Virulence 1 41342228
2025 YTHDC2 inhibits the resistance of lung cancer to EGFR-TKI through cuproptosis. Oncogene 1 41402633
2024 YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation. bioRxiv : the preprint server for biology 1 36747642
2020 1H, 13C and 15N resonance assignment of the YTH domain of YTHDC2. Biomolecular NMR assignments 1 32930954
2026 YTHDC2-mediated RAB20 degradation regulates NLRP3 inflammasome priming to improve chronic glomerulonephritis. Gene 0 41587667
2026 Fuzheng Shengbai decoction enhances antitumor immunity via YTHDC2-dependent stabilization of CLCA2 mRNA in colorectal cancer. Journal of ethnopharmacology 0 41616882
2026 YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis. Inflammation 0 41811549
2026 Novel variants in YTHDC2 cause non-obstructive azoospermia by disrupting the mitotic-to-meiotic transition in humans and mice. Human reproduction (Oxford, England) 0 42249589
2025 YTHDC2 inhibits HPV-positive cervical cancer growth by suppressing SLC7A11 in a ferroptosis-dependent manner. Oncology letters 0 40917727
2025 YTHDC2 suppresses bladder cancer by inhibiting SOX2-mediated tumor plasticity. Cell death & disease 0 41145440
2025 Cigarette smoke-mediated YTHDC2 suppression drives macrophage senescence and a tumor-promoting microenvironment in lung cancer. Immunology and cell biology 0 41292214
2024 AC092100.1 promotes angiogenesis in pre-eclampsia through YTHDC2/VEGFA signaling. Functional & integrative genomics 0 39237822
2024 Downregulation of the m6A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members. The Journal of biological chemistry 0 39303913
2022 Construction and clinical evaluation of N6-methyladenosine risk signature of YTHDC2, IGF2BP2, and HNRNPC in head and neck squamous cell carcinoma. Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology 0 36416324

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