{"gene":"YTHDC2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"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.","method":"m6A binding assays, knockout mouse model, translational efficiency assays, mRNA abundance measurements","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, KO mouse with defined cellular phenotype, independently replicated across multiple labs","pmids":["28809393"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro ATPase and helicase assays, biochemical interaction studies (ankyrin repeat-XRN1 interaction), high-throughput m6A transcriptome mapping, mutant testes expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution of helicase activity, domain mapping of XRN1 interaction, replicated in subsequent studies","pmids":["29033321"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Knockout mouse model, immunofluorescence, RNA binding assays, co-immunoprecipitation with RNA granule components","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with specific cellular phenotype, RNA binding shown, replicated across labs","pmids":["29087293"],"is_preprint":false},{"year":2018,"finding":"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).","method":"Domain deletion analysis, RNA binding assays, CRAC (crosslinking and analysis of cDNA), co-immunoprecipitation with ribosomal subunits","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (CRAC, domain mutants, pulldown), single lab but rigorous domain dissection","pmids":["29970596"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ENU mutagenesis screen, missense mutant mouse model, in vitro helicase assay, subcellular fractionation/immunofluorescence for cytoplasmic localization, genetic epistasis with MEIOC mutants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro helicase assay, genetic screen with defined mutation, epistasis with MEIOC, evolutionary analysis","pmids":["29360036"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Ribosome profiling, RNA structure analysis, YTHDC2 knockdown with translational efficiency measurements, luciferase reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ribosome profiling plus KD rescue, multiple orthogonal methods, single lab","pmids":["31767846"],"is_preprint":false},{"year":2019,"finding":"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.","method":"X-ray crystallography","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination, single lab but direct structural evidence","pmids":["31472957"],"is_preprint":false},{"year":2020,"finding":"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.","method":"NMR spectroscopy (1H, 13C, 15N resonance assignment), solution structure determination","journal":"Biomolecular NMR assignments","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure solved, single lab, no functional mutagenesis validation in this paper","pmids":["32930954"],"is_preprint":false},{"year":2021,"finding":"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.","method":"RIP assay, mRNA stability assays, m6A-dependent RNA binding validation, YTH domain mutant analysis, mouse xenograft/PDX models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability assay plus domain mutant, single lab, two orthogonal methods","pmids":["33232910"],"is_preprint":false},{"year":2021,"finding":"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.","method":"YTHDC2 knockdown/overexpression, RIP assay demonstrating physical binding to IGF1R mRNA, luciferase reporter for translation initiation, in vitro and in vivo radioresistance assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP plus reporter assay plus cellular phenotype, single lab, limited mechanistic depth","pmids":["32850334"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional knockout mouse model, single-cell transcriptomics, CLIP-seq for YTHDC2 binding sites, microtubule inhibitor rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined pachytene phenotype, CLIP-seq for binding sites, single-cell transcriptomics, multiple orthogonal methods","pmids":["34910909"],"is_preprint":false},{"year":2021,"finding":"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.","method":"m6A consensus motif mutagenesis, luciferase reporter assays for IRES-mediated translation, helicase-dead mutant (E332Q) functional analysis, RNA-protein interaction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of catalytic residue, IRES reporter assay, m6A site-specific mutation, single lab with multiple orthogonal methods","pmids":["33649237"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro helicase reconstitution, multiple knock-in mouse models with defined mutations, CLIP-seq, zebrafish replication, multiple orthogonal methods","pmids":["35305312"],"is_preprint":false},{"year":2022,"finding":"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.","method":"m6A-binding pocket mutant knock-in mice, ATPase motif mutant knock-in mice, CLIP-seq for binding site mapping, whole-testis ribosome profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple knock-in mouse models with domain-specific mutations, CLIP-seq, ribosome profiling; independently corroborates Li et al. 2022","pmids":["35058317"],"is_preprint":false},{"year":2022,"finding":"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.","method":"m6A mapping during KSHV infection, YTHDC2 knockdown, RIP assay for YTHDC2 binding to IL-6 mRNA, m6A mutant reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus m6A mutant reporters plus KD phenotype, single lab, two orthogonal methods","pmids":["35177478"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Whole-exome sequencing, protein structural modeling, expression analysis in human fetal ovary, functional domain mapping","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human genetics plus structural modeling plus expression data, single study, limited functional reconstitution","pmids":["35138268"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation for trimer complex, chromatin immunoprecipitation (ChIP) for transcription factor binding, siRNA knockdown, HDAC inhibitor (TSA) treatment, luciferase promoter assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for complex, ChIP for transcriptional regulation, single lab, two orthogonal methods","pmids":["24269672"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown, luciferase reporter with HIF-1α 5'UTR, metastasis assays in vitro and in vivo, western blotting","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay plus KD phenotype plus in vivo, single lab, limited mechanistic depth on helicase mechanism","pmids":["26996300"],"is_preprint":false},{"year":2021,"finding":"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.","method":"RIP assay, m6A methylation assay, polysome profiling for translational efficiency, CRISPR-KO, ChIP for YAP/TEAD binding at YTHDC2 promoter, luciferase reporter","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus polysome profiling plus ChIP, single lab, multiple orthogonal methods","pmids":["34911015"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RIP assay, mRNA stability assay, m6A-IP, YTHDC2 knockdown/overexpression, eIF2α phosphorylation assays, stress granule imaging","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability plus m6A-IP, single lab, multiple methods","pmids":["37778684"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — novel pull-down method, KO mouse, RIP demonstrating ISG20 recruitment, multiple orthogonal methods in single lab","pmids":["37776518"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Rod-specific conditional KO mouse, ERG recordings, RIP assay, m6A-IP, polysome profiling, multi-omics analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with functional phenotype, RIP plus polysome profiling, single lab","pmids":["38157933"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability plus translation assays, single lab, multiple methods","pmids":["35716070"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional (inducible) knockout mouse model, immunofluorescence for meiotic markers, co-immunoprecipitation for RNA-binding protein interactions","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with temporal control plus co-IP, peer-reviewed and corroborated by preprint version","pmids":["39378093"],"is_preprint":false},{"year":2024,"finding":"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.","method":"m6A-IP, RIP assay for YTHDC2 binding to SCD1 mRNA, mRNA stability assay, METTL16 overexpression/knockout","journal":"Cellular and molecular life sciences : CMLS","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP-based binding claim without deep mechanistic follow-up on YTHDC2 specifically","pmids":["38334797"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RIP-qPCR for YTHDC2-NCOA4 mRNA binding, mRNA stability assay, METTL3 silencing, overexpression in ICH rat model","journal":"Epigenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP plus stability assay, limited mechanistic depth on YTHDC2 helicase mechanism","pmids":["38465865"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RIP assay for YTHDC2-AMIGO2 mRNA interaction, MeRIP for m6A level on AMIGO2, siRNA knockdown of METTL3/YTHDC2, AMIGO2 overexpression rescue","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP plus MeRIP, no deep mechanistic follow-up on YTHDC2 enzymatic activity","pmids":["38432455"],"is_preprint":false},{"year":2024,"finding":"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.","method":"RIP assay, RNA pull-down, dual-luciferase reporter assay, mRNA stability assay, me-RIP for KDM5B m6A levels, XF96 metabolic flux analysis","journal":"Acta diabetologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP plus mRNA stability assay, functional link to mitochondrial metabolism indirect","pmids":["36574062"],"is_preprint":false},{"year":2025,"finding":"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.","method":"m6A site mutagenesis, RIP assay, mRNA stability assay, YTHDC2 KO/OE in cell lines and PDX models, cuproptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A site-specific mutagenesis plus RIP plus mRNA stability plus in vivo PDX model, single lab","pmids":["41402633"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Whole-exome sequencing of patient cohort, CRISPR/Cas9 knock-in mouse model, spermatocyte spreading, immunofluorescence for meiotic/mitotic markers, quantitative RT-PCR, western blotting","journal":"Human reproduction (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics validated by knock-in mouse model, multiple orthogonal methods, consistent with prior MEIOC epistasis data","pmids":["42249589"],"is_preprint":false},{"year":2026,"finding":"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.","method":"RNA immunoprecipitation (RIP), mRNA stability assay, YTHDC2 overexpression/knockdown, DSS colitis mouse model, in vitro LPS model","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP plus stability assay, limited mechanistic depth on YTHDC2 mechanism","pmids":["41811549"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Deep learning-based drug discovery (EPMolGen), in vitro binding/inhibition assays (IC50 measurement), cellular target engagement assays, selectivity profiling over other YTH proteins","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro IC50 assay plus cellular target engagement, single lab, novel first-in-class inhibitor","pmids":["41495018"],"is_preprint":false}],"current_model":"YTHDC2 is a large, multidomain cytoplasmic RNA helicase and m6A reader that binds m6A-containing and U-rich/UG-rich RNA sequences through its YTH and R3H domains; its 3'→5' helicase activity (ATPase-dependent, enhanced by interaction of its ankyrin repeats with the 5'→3' exonuclease XRN1) is essential for mammalian fertility by enabling the mitosis-to-meiosis transcriptome switch in germ cells and sustaining meiotic progression through pachytene—functions that are independent of m6A recognition in vivo—while in somatic contexts YTHDC2 regulates translation efficiency (by unwinding 5'-UTR and CDS secondary structures), mRNA stability (targeting transcripts for XRN1-mediated decay), and innate immune termination (by recruiting ISG20 to degrade IFN-β mRNA), with its YTH domain structurally characterized by crystal structure and NMR, and its transcription controlled by c-Jun/ATF-2 at a CRE promoter element."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2017,"claim":"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","pmids":["28809393"],"confidence":"High","gaps":["Did not separate m6A-reading from helicase activity as the basis of the fertility phenotype","Direct enzymatic activity not yet reconstituted"]},{"year":2017,"claim":"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","pmids":["29033321"],"confidence":"High","gaps":["Quantitative contribution of XRN1 to in vivo target decay not established","Relationship between helicase activity and m6A reading unresolved"]},{"year":2017,"claim":"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","pmids":["29087293"],"confidence":"High","gaps":["Whether Ccna2 clearance is direct via decay versus indirect not fully resolved","RNA granule partner identities only partially defined"]},{"year":2018,"claim":"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","pmids":["29970596"],"confidence":"High","gaps":["Functional consequence of small-subunit association not mechanistically tied to translation outcomes","Single-lab structural inference"]},{"year":2018,"claim":"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","pmids":["29360036"],"confidence":"High","gaps":["Molecular nature of the MEIOC-YTHDC2 functional partnership not defined","Mechanism of premature metaphase entry unresolved"]},{"year":2019,"claim":"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","pmids":["31767846"],"confidence":"High","gaps":["Direct demonstration that YTHDC2 unwinds CDS structure in vitro not shown here","Single-lab"]},{"year":2019,"claim":"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","pmids":["31472957"],"confidence":"High","gaps":["Structure of full-length protein or helicase domain not determined","No RNA-bound complex structure"]},{"year":2020,"claim":"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","pmids":["32930954"],"confidence":"Medium","gaps":["No functional mutagenesis validation in this study","Selectivity consequences of loop differences not tested"]},{"year":2021,"claim":"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","pmids":["33232910","32850334","34911015"],"confidence":"Medium","gaps":["Determinants selecting decay versus translation outcomes unknown","Generalizability beyond individual cancer lines unclear"]},{"year":2021,"claim":"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","pmids":["34910909"],"confidence":"High","gaps":["Mechanism linking transcript clearance to telomere clustering not defined","Why m6A status fails to predict targets unresolved at this stage"]},{"year":2021,"claim":"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","pmids":["33649237"],"confidence":"High","gaps":["Role of host cofactors beyond La antigen not mapped","Single-lab"]},{"year":2022,"claim":"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","pmids":["35305312","35058317"],"confidence":"High","gaps":["How sequence specificity (U-rich) is encoded without m6A reading unresolved","Dominant-negative mechanism of catalytic-dead mutant not structurally explained"]},{"year":2022,"claim":"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","pmids":["35177478"],"confidence":"Medium","gaps":["Mechanism of protection versus its decay-promoting activity unresolved","Single-lab"]},{"year":2022,"claim":"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","pmids":["35138268"],"confidence":"Medium","gaps":["Functional reconstitution of variant effects limited","Causality not tested in an animal model in this study"]},{"year":2023,"claim":"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","pmids":["37776518"],"confidence":"High","gaps":["Structural basis of ISG20 recruitment versus XRN1 recruitment unknown","Whether helicase activity is required for IFN-β degradation not dissected"]},{"year":2024,"claim":"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","pmids":["39378093"],"confidence":"High","gaps":["Distinct molecular targets at the pachytene-to-diplotene step not enumerated","Granule composition only partially defined"]},{"year":2024,"claim":"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","pmids":["35716070","38157933","38334797","38465865","38432455","36574062"],"confidence":"Medium","gaps":["Several individual-target studies are low-confidence single-lab RIP-based claims","Whether helicase activity drives these outcomes generally untested"]},{"year":2026,"claim":"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","pmids":["42249589"],"confidence":"High","gaps":["Direct biochemical effect of each variant on helicase activity not measured","How partner loss is mechanistically caused by variants unresolved"]},{"year":2025,"claim":"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","pmids":["41495018"],"confidence":"Medium","gaps":["Inhibitor targets m6A pocket, which is dispensable for germline function, limiting relevance to that role","In vivo efficacy not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,8,12,13]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4,11,12]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,12,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,12]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,5,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,12,20]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2,12,15,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,17]},{"term_id":"R-HSA-168256","term_label":"Immune 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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 (PubMed:26318451, PubMed:29033321). Essential for ensuring a successful progression of the meiotic program in the germline by regulating the level of m6A-containing RNAs (By similarity). 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 (PubMed:29033321). 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learning-assisted discovery of a potent and cell-active inhibitor of RNA N6-methyladenosine recognition protein YTHDC2.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41495018","citation_count":1,"is_preprint":false},{"pmid":"40049308","id":"PMC_40049308","title":"Identification and functional regulation of three alternative splicing isoforms of the Ythdc2 gene in Miichthysmiiuy.","date":"2025","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40049308","citation_count":1,"is_preprint":false},{"pmid":"32930954","id":"PMC_32930954","title":"1H, 13C and 15N resonance assignment of the YTH domain of YTHDC2.","date":"2020","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/32930954","citation_count":1,"is_preprint":false},{"pmid":"41145440","id":"PMC_41145440","title":"YTHDC2 suppresses bladder cancer by inhibiting SOX2-mediated tumor plasticity.","date":"2025","source":"Cell death 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/40917727","citation_count":0,"is_preprint":false},{"pmid":"39303913","id":"PMC_39303913","title":"Downregulation of the m6A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39303913","citation_count":0,"is_preprint":false},{"pmid":"41587667","id":"PMC_41587667","title":"YTHDC2-mediated RAB20 degradation regulates NLRP3 inflammasome priming to improve chronic glomerulonephritis.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41587667","citation_count":0,"is_preprint":false},{"pmid":"41292214","id":"PMC_41292214","title":"Cigarette smoke-mediated YTHDC2 suppression drives macrophage senescence and a tumor-promoting microenvironment in lung cancer.","date":"2025","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41292214","citation_count":0,"is_preprint":false},{"pmid":"42249589","id":"PMC_42249589","title":"Novel variants in YTHDC2 cause non-obstructive azoospermia by disrupting the mitotic-to-meiotic transition in humans and mice.","date":"2026","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/42249589","citation_count":0,"is_preprint":false},{"pmid":"41616882","id":"PMC_41616882","title":"Fuzheng Shengbai decoction enhances antitumor immunity via YTHDC2-dependent stabilization of CLCA2 mRNA in colorectal cancer.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41616882","citation_count":0,"is_preprint":false},{"pmid":"41811549","id":"PMC_41811549","title":"YTHDC2 Deficiency Exacerbates Ulcerative Colitis by Stabilizing RBMS1 mRNA to Drive Epithelial Ferroptosis.","date":"2026","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41811549","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.17.676462","title":"Evolutionary patterns and repeated adaptive strategies of deep-sea anemones","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676462","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.14.24317129","title":"Comprehensive analysis of key m6A RNA modification-related genes and immune infiltrates in hypertrophic cardiomyopathy","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.14.24317129","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37539,"output_tokens":8393,"usd":0.119256,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18079,"output_tokens":5618,"usd":0.115422,"stage2_stop_reason":"end_turn"},"total_usd":0.234678,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"m6A binding assays, knockout mouse model, translational efficiency assays, mRNA abundance measurements\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, KO mouse with defined cellular phenotype, independently replicated across multiple labs\",\n      \"pmids\": [\"28809393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ATPase and helicase assays, biochemical interaction studies (ankyrin repeat-XRN1 interaction), high-throughput m6A transcriptome mapping, mutant testes expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution of helicase activity, domain mapping of XRN1 interaction, replicated in subsequent studies\",\n      \"pmids\": [\"29033321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse model, immunofluorescence, RNA binding assays, co-immunoprecipitation with RNA granule components\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with specific cellular phenotype, RNA binding shown, replicated across labs\",\n      \"pmids\": [\"29087293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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).\",\n      \"method\": \"Domain deletion analysis, RNA binding assays, CRAC (crosslinking and analysis of cDNA), co-immunoprecipitation with ribosomal subunits\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (CRAC, domain mutants, pulldown), single lab but rigorous domain dissection\",\n      \"pmids\": [\"29970596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ENU mutagenesis screen, missense mutant mouse model, in vitro helicase assay, subcellular fractionation/immunofluorescence for cytoplasmic localization, genetic epistasis with MEIOC mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro helicase assay, genetic screen with defined mutation, epistasis with MEIOC, evolutionary analysis\",\n      \"pmids\": [\"29360036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Ribosome profiling, RNA structure analysis, YTHDC2 knockdown with translational efficiency measurements, luciferase reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling plus KD rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31767846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination, single lab but direct structural evidence\",\n      \"pmids\": [\"31472957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"NMR spectroscopy (1H, 13C, 15N resonance assignment), solution structure determination\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure solved, single lab, no functional mutagenesis validation in this paper\",\n      \"pmids\": [\"32930954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"RIP assay, mRNA stability assays, m6A-dependent RNA binding validation, YTH domain mutant analysis, mouse xenograft/PDX models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability assay plus domain mutant, single lab, two orthogonal methods\",\n      \"pmids\": [\"33232910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"YTHDC2 knockdown/overexpression, RIP assay demonstrating physical binding to IGF1R mRNA, luciferase reporter for translation initiation, in vitro and in vivo radioresistance assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP plus reporter assay plus cellular phenotype, single lab, limited mechanistic depth\",\n      \"pmids\": [\"32850334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse model, single-cell transcriptomics, CLIP-seq for YTHDC2 binding sites, microtubule inhibitor rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined pachytene phenotype, CLIP-seq for binding sites, single-cell transcriptomics, multiple orthogonal methods\",\n      \"pmids\": [\"34910909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"m6A consensus motif mutagenesis, luciferase reporter assays for IRES-mediated translation, helicase-dead mutant (E332Q) functional analysis, RNA-protein interaction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of catalytic residue, IRES reporter assay, m6A site-specific mutation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33649237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro helicase reconstitution, multiple knock-in mouse models with defined mutations, CLIP-seq, zebrafish replication, multiple orthogonal methods\",\n      \"pmids\": [\"35305312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"m6A-binding pocket mutant knock-in mice, ATPase motif mutant knock-in mice, CLIP-seq for binding site mapping, whole-testis ribosome profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple knock-in mouse models with domain-specific mutations, CLIP-seq, ribosome profiling; independently corroborates Li et al. 2022\",\n      \"pmids\": [\"35058317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"m6A mapping during KSHV infection, YTHDC2 knockdown, RIP assay for YTHDC2 binding to IL-6 mRNA, m6A mutant reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus m6A mutant reporters plus KD phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"35177478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing, protein structural modeling, expression analysis in human fetal ovary, functional domain mapping\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human genetics plus structural modeling plus expression data, single study, limited functional reconstitution\",\n      \"pmids\": [\"35138268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation for trimer complex, chromatin immunoprecipitation (ChIP) for transcription factor binding, siRNA knockdown, HDAC inhibitor (TSA) treatment, luciferase promoter assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for complex, ChIP for transcriptional regulation, single lab, two orthogonal methods\",\n      \"pmids\": [\"24269672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, luciferase reporter with HIF-1α 5'UTR, metastasis assays in vitro and in vivo, western blotting\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay plus KD phenotype plus in vivo, single lab, limited mechanistic depth on helicase mechanism\",\n      \"pmids\": [\"26996300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"RIP assay, m6A methylation assay, polysome profiling for translational efficiency, CRISPR-KO, ChIP for YAP/TEAD binding at YTHDC2 promoter, luciferase reporter\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus polysome profiling plus ChIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34911015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RIP assay, mRNA stability assay, m6A-IP, YTHDC2 knockdown/overexpression, eIF2α phosphorylation assays, stress granule imaging\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability plus m6A-IP, single lab, multiple methods\",\n      \"pmids\": [\"37778684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel pull-down method, KO mouse, RIP demonstrating ISG20 recruitment, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"37776518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Rod-specific conditional KO mouse, ERG recordings, RIP assay, m6A-IP, polysome profiling, multi-omics analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with functional phenotype, RIP plus polysome profiling, single lab\",\n      \"pmids\": [\"38157933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability plus translation assays, single lab, multiple methods\",\n      \"pmids\": [\"35716070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional (inducible) knockout mouse model, immunofluorescence for meiotic markers, co-immunoprecipitation for RNA-binding protein interactions\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with temporal control plus co-IP, peer-reviewed and corroborated by preprint version\",\n      \"pmids\": [\"39378093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"m6A-IP, RIP assay for YTHDC2 binding to SCD1 mRNA, mRNA stability assay, METTL16 overexpression/knockout\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP-based binding claim without deep mechanistic follow-up on YTHDC2 specifically\",\n      \"pmids\": [\"38334797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RIP-qPCR for YTHDC2-NCOA4 mRNA binding, mRNA stability assay, METTL3 silencing, overexpression in ICH rat model\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP plus stability assay, limited mechanistic depth on YTHDC2 helicase mechanism\",\n      \"pmids\": [\"38465865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RIP assay for YTHDC2-AMIGO2 mRNA interaction, MeRIP for m6A level on AMIGO2, siRNA knockdown of METTL3/YTHDC2, AMIGO2 overexpression rescue\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP plus MeRIP, no deep mechanistic follow-up on YTHDC2 enzymatic activity\",\n      \"pmids\": [\"38432455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"RIP assay, RNA pull-down, dual-luciferase reporter assay, mRNA stability assay, me-RIP for KDM5B m6A levels, XF96 metabolic flux analysis\",\n      \"journal\": \"Acta diabetologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP plus mRNA stability assay, functional link to mitochondrial metabolism indirect\",\n      \"pmids\": [\"36574062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"m6A site mutagenesis, RIP assay, mRNA stability assay, YTHDC2 KO/OE in cell lines and PDX models, cuproptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A site-specific mutagenesis plus RIP plus mRNA stability plus in vivo PDX model, single lab\",\n      \"pmids\": [\"41402633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing of patient cohort, CRISPR/Cas9 knock-in mouse model, spermatocyte spreading, immunofluorescence for meiotic/mitotic markers, quantitative RT-PCR, western blotting\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics validated by knock-in mouse model, multiple orthogonal methods, consistent with prior MEIOC epistasis data\",\n      \"pmids\": [\"42249589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assay, YTHDC2 overexpression/knockdown, DSS colitis mouse model, in vitro LPS model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP plus stability assay, limited mechanistic depth on YTHDC2 mechanism\",\n      \"pmids\": [\"41811549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Deep learning-based drug discovery (EPMolGen), in vitro binding/inhibition assays (IC50 measurement), cellular target engagement assays, selectivity profiling over other YTH proteins\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro IC50 assay plus cellular target engagement, single lab, novel first-in-class inhibitor\",\n      \"pmids\": [\"41495018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDC2 is a large, multidomain cytoplasmic RNA helicase and m6A reader that binds m6A-containing and U-rich/UG-rich RNA sequences through its YTH and R3H domains; its 3'→5' helicase activity (ATPase-dependent, enhanced by interaction of its ankyrin repeats with the 5'→3' exonuclease XRN1) is essential for mammalian fertility by enabling the mitosis-to-meiosis transcriptome switch in germ cells and sustaining meiotic progression through pachytene—functions that are independent of m6A recognition in vivo—while in somatic contexts YTHDC2 regulates translation efficiency (by unwinding 5'-UTR and CDS secondary structures), mRNA stability (targeting transcripts for XRN1-mediated decay), and innate immune termination (by recruiting ISG20 to degrade IFN-β mRNA), with its YTH domain structurally characterized by crystal structure and NMR, and its transcription controlled by c-Jun/ATF-2 at a CRE promoter element.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2, #12]. It recognizes m6A through a YTH domain bearing a conserved hydrophobic binding pocket, while its R3H domain contributes additional cellular RNA binding [#0, #3]. The protein possesses RNA-induced, ATP-dependent 3'\\u21925' helicase activity, and recruits the 5'\\u21923' 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 [#1, #12]. 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 [#12, #13]. 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 [#2, #4, #23, #29]. 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 [#1, #5, #17], and it terminates antiviral innate immunity by recruiting the exonuclease ISG20 to degrade m6A-modified IFN-\\u03b2 mRNA [#20]. 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 [#15, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established YTHDC2 as an m6A reader required for spermatogenesis, linking m6A recognition to both translational enhancement and reduced mRNA abundance of targets.\",\n      \"evidence\": \"m6A binding assays, translational efficiency and mRNA abundance measurements, Ythdc2 knockout mice with germ cell arrest\",\n      \"pmids\": [\"28809393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate m6A-reading from helicase activity as the basis of the fertility phenotype\", \"Direct enzymatic activity not yet reconstituted\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the enzymatic and decay-coupling machinery of YTHDC2, showing it is an ATP-dependent 3'\\u21925' helicase that recruits XRN1 to degrade germline transcripts.\",\n      \"evidence\": \"In vitro ATPase/helicase reconstitution, domain mapping of the ankyrin-XRN1 interaction, m6A transcriptome mapping in testes\",\n      \"pmids\": [\"29033321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of XRN1 to in vivo target decay not established\", \"Relationship between helicase activity and m6A reading unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed YTHDC2 enforces a clean mitosis-to-meiosis switch by clearing mitotic regulators, defining its developmental function.\",\n      \"evidence\": \"Knockout mouse, immunofluorescence for meiotic markers, RNA binding and co-IP with RNA granule components\",\n      \"pmids\": [\"29087293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ccna2 clearance is direct via decay versus indirect not fully resolved\", \"RNA granule partner identities only partially defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain deletion analysis, RNA binding assays, CRAC, ribosomal subunit co-IP\",\n      \"pmids\": [\"29970596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of small-subunit association not mechanistically tied to translation outcomes\", \"Single-lab structural inference\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A missense (ketu) allele and MEIOC epistasis established YTHDC2 as a cytoplasmic helicase acting with MEIOC, with evolutionary conservation across metazoans.\",\n      \"evidence\": \"ENU mutagenesis screen, missense knock-in mouse, in vitro helicase assay, genetic epistasis with MEIOC, phylogenetics\",\n      \"pmids\": [\"29360036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the MEIOC-YTHDC2 functional partnership not defined\", \"Mechanism of premature metaphase entry unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected YTHDC2 helicase function to translation elongation, showing it resolves CDS secondary structure marked by m6A.\",\n      \"evidence\": \"Ribosome profiling, RNA structure analysis, knockdown with translational efficiency and reporter assays\",\n      \"pmids\": [\"31767846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that YTHDC2 unwinds CDS structure in vitro not shown here\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided structural basis for m6A recognition, defining the YTH domain pocket shared in architecture with other YTH readers.\",\n      \"evidence\": \"X-ray crystallography of the human YTHDC2 YTH domain\",\n      \"pmids\": [\"31472957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length protein or helicase domain not determined\", \"No RNA-bound complex structure\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined the YTH domain solution architecture, showing distinct \\u03b24-\\u03b25 loop features versus YTHDC1 that shape its m6A pocket.\",\n      \"evidence\": \"NMR resonance assignment and solution topology\",\n      \"pmids\": [\"32930954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mutagenesis validation in this study\", \"Selectivity consequences of loop differences not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed YTHDC2 can both destabilize and translationally activate distinct m6A targets in somatic cancer contexts, broadening its post-transcriptional repertoire.\",\n      \"evidence\": \"RIP, mRNA stability and polysome/luciferase assays, YTH mutants, xenograft/PDX models across SLC7A11, IGF1R, YAP\",\n      \"pmids\": [\"33232910\", \"32850334\", \"34911015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants selecting decay versus translation outcomes unknown\", \"Generalizability beyond individual cancer lines unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a pachytene-stage requirement and confirmed YTHDC2 primarily targets transcripts for degradation, with germline dysregulation uncorrelated to m6A status.\",\n      \"evidence\": \"Conditional knockout, single-cell transcriptomics, CLIP-seq, microtubule inhibitor rescue\",\n      \"pmids\": [\"34910909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking transcript clearance to telomere clustering not defined\", \"Why m6A status fails to predict targets unresolved at this stage\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated YTHDC2 in viral RNA translation, showing helicase activity supports HCV IRES-dependent initiation at an m6A site.\",\n      \"evidence\": \"m6A site mutagenesis, IRES luciferase reporters, helicase-dead E332Q mutant\",\n      \"pmids\": [\"33649237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of host cofactors beyond La antigen not mapped\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"35305312\", \"35058317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sequence specificity (U-rich) is encoded without m6A reading unresolved\", \"Dominant-negative mechanism of catalytic-dead mutant not structurally explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"m6A mapping, RIP, m6A mutant reporters, knockdown during KSHV lytic infection\",\n      \"pmids\": [\"35177478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of protection versus its decay-promoting activity unresolved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked YTHDC2 to human reproductive disease, associating pathogenic helicase-region variants with primary ovarian insufficiency.\",\n      \"evidence\": \"Whole-exome sequencing, structural modeling, human fetal ovary expression\",\n      \"pmids\": [\"35138268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional reconstitution of variant effects limited\", \"Causality not tested in an animal model in this study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an innate-immune termination function, showing YTHDC2 recruits ISG20 to degrade m6A-modified IFN-\\u03b2 mRNA late in infection.\",\n      \"evidence\": \"Enzymolysis-based RNA pull-down, KO mouse, RIP for ISG20 interaction, in vitro and in vivo viral infection\",\n      \"pmids\": [\"37776518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ISG20 recruitment versus XRN1 recruitment unknown\", \"Whether helicase activity is required for IFN-\\u03b2 degradation not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a second, post-meiotic-prophase requirement for YTHDC2 and reinforced its collaboration with RNA-granule RNA-binding proteins including MEIOC.\",\n      \"evidence\": \"Inducible conditional knockout, immunofluorescence for meiotic markers, co-IP for RNA-binding partners\",\n      \"pmids\": [\"39378093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct molecular targets at the pachytene-to-diplotene step not enumerated\", \"Granule composition only partially defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded m6A-dependent target regulation to neural, retinal, and metabolic contexts, showing tissue-specific translational enhancement and decay of distinct mRNAs.\",\n      \"evidence\": \"Conditional KO (rod-specific), RIP, polysome profiling, m6A-IP, mRNA stability assays across Lrp2, Ppef2/Pde6b, and somatic targets\",\n      \"pmids\": [\"35716070\", \"38157933\", \"38334797\", \"38465865\", \"38432455\", \"36574062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several individual-target studies are low-confidence single-lab RIP-based claims\", \"Whether helicase activity drives these outcomes generally untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed YTHDC2 as a human azoospermia gene and mechanistically tied disease variants to loss of MEIOC/RBM46 and failed mitotic-gene clearance.\",\n      \"evidence\": \"Patient whole-exome sequencing, CRISPR knock-in mouse recapitulating arrest, marker immunofluorescence, qRT-PCR, western blotting\",\n      \"pmids\": [\"42249589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical effect of each variant on helicase activity not measured\", \"How partner loss is mechanistically caused by variants unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated pharmacological tractability of the YTH m6A pocket with a selective small-molecule inhibitor that reduces target mRNA expression.\",\n      \"evidence\": \"Deep-learning drug design, in vitro IC50, cellular target engagement and selectivity profiling\",\n      \"pmids\": [\"41495018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor targets m6A pocket, which is dispensable for germline function, limiting relevance to that role\", \"In vivo efficacy not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 8, 12, 13]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4, 11, 12]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 12, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 5, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 12, 20]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2, 12, 15, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [20, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"XRN1\", \"MEIOC\", \"RBM46\", \"ISG20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}