{"gene":"DHX37","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2015,"finding":"The DEAH-box helicase Dhr1 (yeast ortholog of DHX37) is responsible for displacing U3 snoRNA from the pre-ribosome. An active-site mutant of Dhr1 blocked U3 release, trapping a pre-40S particle containing U3, pre-rRNA, and early-acting assembly factors but lacking ribosomal proteins surrounding the central pseudoknot. In vivo crosslinking showed Dhr1 contacts pre-rRNA and U3 sequences flanking regions that base-pair to form the central pseudoknot. Point mutations in the U3 box A region suppressed a cold-sensitive Dhr1 mutation, indicating U3 is an in vivo substrate. Dhr1 was also shown to unwind U3-18S duplexes in vitro.","method":"Active-site mutagenesis, in vivo crosslinking (CRAC), genetic suppressor analysis, in vitro unwinding assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (mutagenesis, crosslinking, genetic suppression, in vitro reconstitution) in a single rigorous study, independently confirmed by later work","pmids":["25710520"],"is_preprint":false},{"year":2016,"finding":"Utp14 recruits and activates Dhr1 (yeast DHX37 ortholog) at the preribosome. Utp14 forms a complex with Dhr1 and directly stimulates its RNA-unwinding activity in vitro. Mutations in a discrete region of Utp14 reduced Dhr1 interaction and phenocopied a helicase-inactive Dhr1 mutant (accumulation of Dhr1 and U3 in a pre-40S particle). Stable association of Dhr1 with the preribosome requires both Utp14 and Bud23, revealing that Utp14 is bifunctional: it recruits Dhr1 (together with Bud23) and activates its unwinding activity.","method":"In vitro unwinding stimulation assay, co-immunoprecipitation, genetic epistasis with bud23 and utp14 mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical reconstitution of activation plus reciprocal genetic and interaction data, replicated in subsequent human studies","pmids":["26729466"],"is_preprint":false},{"year":2018,"finding":"Human DHX37 is required for maturation of the small ribosomal subunit. In vivo crosslinking showed DHX37 binds directly to U3 snoRNA, and its catalytic activity is required for dissociation of U3 snoRNA from pre-ribosomal complexes, enabling central pseudoknot formation. Failure to recruit DHX37 to early pre-ribosomal particles triggers a quality-control pathway leading to pre-rRNA degradation. UTP14A was identified as a direct interaction partner of DHX37 that acts as a cofactor stimulating helicase activity in the context of U3 snoRNA release.","method":"In vivo UV crosslinking (CRAC), catalytic-dead mutant analysis, co-immunoprecipitation, siRNA knockdown with pre-rRNA processing readout","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (crosslinking, mutagenesis, interaction mapping, knockdown phenotype) in human cells, consistent with yeast findings","pmids":["30582406"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of human DHX37 in complex with single-stranded RNA was solved, revealing a canonical DEAH ATPase/helicase architecture and a structurally unique carboxy-terminal domain (CTD). Structural comparisons with ATP-analog-bound DEAH helicases suggest ATP-dependent 3'-to-5' RNA translocation via a register shift in bound RNA. A conserved sequence motif in UTP14A directly interacts with DHX37, stimulating its ATPase activity and enhancing RNA binding. The CTD of DHX37 is required (but not sufficient) for interaction with UTP14A in vitro and is essential for ribosome biogenesis in vivo.","method":"X-ray crystallography, in vitro ATPase assay, mutagenesis, pulldown/interaction mapping","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro biochemical assays and mutagenesis of both DHX37 and UTP14A in a single rigorous study","pmids":["30910870"],"is_preprint":false},{"year":2019,"finding":"The crystal structure of the yeast Dhr1 helicase module was solved, revealing a remarkable carboxy-terminal domain (CTD) essential for Dhr1 function in ribosome biogenesis in vivo and important for interaction with its coactivator Utp14 in vitro. DHX37 patient mutations (associated with microcephaly and neurological disease) mapped to this structure show functional consequences on ribosome biogenesis.","method":"X-ray crystallography, in vivo functional rescue assays, in vitro interaction assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vivo and in vitro functional validation, single lab but multiple orthogonal methods","pmids":["31188444"],"is_preprint":false},{"year":2022,"finding":"Purified Dhr1 (yeast DHX37 ortholog) is an active RNA-dependent ATPase with specific RNA-unwinding activity in vitro. The N-terminus and an internal loop within the RecA2 domain are autoinhibitory elements. Utp14 can activate the ATPase activity of Dhr1 lacking the autoinhibitory N-terminal loop but not full-length Dhr1, and Utp14 activates Dhr1 by binding to the surface of the RecA1 and RecA2 domains rather than by displacing the inhibitory loop, which is distinct from G-patch protein activation of other DEXH/RHA helicases.","method":"In vitro ATPase assay, unwinding assay, mutagenesis, yeast genetics","journal":"Methods in enzymology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — detailed in vitro biochemical characterization, single lab, protocols paper but contains original data","pmids":["35965019"],"is_preprint":false},{"year":2025,"finding":"Dhr1 N-terminus and an internal loop within the RecA2 domain are autoinhibitory. Utp14 activates Dhr1 by binding to the surface of the RecA1 and RecA2 domains, a mechanism distinct from how G-patch proteins activate other DEXH/RHA helicases. Utp14 activates Dhr1 lacking the autoinhibitory N-terminal loop but not full-length Dhr1, suggesting Utp14 does not relieve autoinhibition by displacing the inhibitory loop.","method":"In vitro ATPase assay, unwinding assay, mutant analysis, yeast genetic complementation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with mutagenesis across multiple constructs, single lab","pmids":["40024476"],"is_preprint":false},{"year":2022,"finding":"DHX37 interacts with PLRG1 and co-occupies the promoter and superenhancer elements of cyclin D1 (CCND1) to transcriptionally activate CCND1 expression in hepatocellular carcinoma cells, promoting cell proliferation. This represents a non-canonical function of DHX37 distinct from its role in ribosome biogenesis.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), epigenomic profiling, knockdown with proliferation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ChIP-seq, and functional knockdown in a single lab; mechanistic claim rests on co-occupancy and interaction data","pmids":["35290436"],"is_preprint":false},{"year":2025,"finding":"DHX37 (also annotated as DDX37) and DDX50 resolve RNA-DNA hybrids (R-loops) that form during transcription, thereby preventing replication stress and DNA damage. Depletion of DHX37 caused increased H2AX phosphorylation, increased comet tail length, decreased replication track length, and RPA focus formation. The increased RNA-DNA hybrids upon DHX37 depletion could be reversed by RNase H1 overexpression, and transcription inhibition prevented R-loop accumulation and DNA damage.","method":"siRNA knockdown, γH2AX immunofluorescence, comet assay, DNA fiber assay, RPA focus formation, RNase H1 rescue, RNA-DNA hybrid immunofluorescence","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts of R-loop and DNA damage phenotypes with RNase H1 rescue, single lab","pmids":["40043837"],"is_preprint":false},{"year":2025,"finding":"In an in vitro cellular model of human Sertoli cell formation, mutant DHX37 (p.R674Q) retains ATPase activity and is not associated with stabilization of cellular β-catenin. Transfection of mutant DHX37 in induced Sertoli-like cells (iSLCs) showed reduced activation of pro-testis genes compared to WT. HyperTRIBE combined with single-cell full-length RNA-sequencing revealed that WT DHX37 targets transcripts associated primarily with cytoskeleton organization, while the mutant DHX37 targets additional transcripts associated with protein degradation and cell death.","method":"ATPase activity assay, HyperTRIBE RNA-binding mapping, single-cell full-length RNA-seq, transfection in iSLCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal RNA-binding and transcriptomic methods in a human cellular model, single preprint lab","pmids":["bio_10.1101_2025.01.10.632330"],"is_preprint":true},{"year":2026,"finding":"Cell-specific Dhx37 knockout in mouse Sertoli cells caused reduced testicular volume, lower testosterone levels, seminiferous tubule vacuolization, reduced cell proliferation, and elevated apoptosis. RIP-seq and RNAi-RNA-seq in Sertoli cells showed Dhx37 safeguards nucleolar integrity and PI3K-AKT signaling, and suppresses p53-driven apoptosis; Dhx37 loss triggers pro-apoptotic splicing. Loss of nucleolar integrity caused FBL to exit the nucleolus and bind MDM2, thereby releasing p53 to promote apoptosis.","method":"Conditional knockout mouse, immunofluorescence, single-nucleus RNA-seq, RIP-seq, RNAi-RNA-seq, Western blotting, qRT-PCR","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple cellular phenotype readouts and mechanistic RNA-seq, single lab","pmids":["41535247"],"is_preprint":false},{"year":2024,"finding":"A novel pathogenic DHX37 variant (p.Arg671Thr) found in a 46,XY DSD patient had no significant effect on intracellular localization of the DHX37 protein but significantly reduced its expression level in vitro, as assessed by immunofluorescence and Western blotting.","method":"Immunofluorescence (subcellular localization), Western blotting (protein level)","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single variant, single lab, limited functional follow-up beyond localization and expression level","pmids":["38769888"],"is_preprint":false}],"current_model":"DHX37 (Dhr1 in yeast) is a DEAH-box RNA helicase that uses ATP-dependent 3'-to-5' translocation—revealed by its crystal structure—to unwind and displace U3 snoRNA from pre-ribosomal particles, enabling central pseudoknot formation and small ribosomal subunit maturation; its activity is regulated by autoinhibitory elements in the N-terminus and RecA2 loop, and is stimulated by its cofactor UTP14A, which binds the RecA1/RecA2 surface and enhances ATPase activity and RNA binding; additionally, DHX37 resolves transcription-associated R-loops to prevent replication stress, and in certain cancer contexts cooperates with PLRG1 to transcriptionally activate cyclin D1 via superenhancer co-occupation."},"narrative":{"mechanistic_narrative":"DHX37 (yeast Dhr1) is a DEAH-box RNA helicase that catalyzes a key remodeling step in small ribosomal subunit biogenesis by ATP-dependently displacing U3 snoRNA from pre-ribosomal particles, thereby licensing formation of the central pseudoknot of the 18S rRNA [PMID:25710520, PMID:30582406]. Its crystal structure reveals a canonical DEAH ATPase/helicase core plus a structurally distinct carboxy-terminal domain that supports 3'-to-5' RNA translocation, is essential for ribosome biogenesis in vivo, and mediates interaction with its cofactor [PMID:30910870, PMID:31188444]. DHX37 activity is held in check by autoinhibitory elements—its N-terminus and an internal RecA2 loop—and is stimulated by UTP14A/Utp14, which binds the RecA1/RecA2 surface to enhance ATPase and RNA-unwinding activity and, together with Bud23, recruits the helicase to the preribosome; this activation mode is distinct from G-patch protein activation of other DEXH/RHA helicases [PMID:26729466, PMID:30910870, PMID:35965019, PMID:40024476]. Beyond ribosome assembly, DHX37 resolves transcription-associated RNA-DNA hybrids (R-loops) to prevent replication stress and DNA damage, a function confirmed by RNase H1 rescue and transcription inhibition [PMID:40043837], and it cooperates with PLRG1 to co-occupy the CCND1 promoter and superenhancer and transcriptionally activate cyclin D1 in hepatocellular carcinoma [PMID:35290436]. In Sertoli cells, DHX37 safeguards nucleolar integrity and suppresses p53-driven apoptosis, with its loss causing FBL to exit the nucleolus, bind MDM2, and release p53; patient-derived missense variants associated with 46,XY disorders of sex development impair DHX37 function or expression [PMID:41535247, PMID:38769888].","teleology":[{"year":2015,"claim":"Established the core enzymatic function of the helicase by identifying U3 snoRNA as its physiological substrate during ribosome assembly, answering what reaction this helicase performs at the preribosome.","evidence":"Active-site mutagenesis, in vivo CRAC crosslinking, genetic suppressor analysis, and in vitro unwinding assays in yeast Dhr1","pmids":["25710520"],"confidence":"High","gaps":["Structural basis of U3 engagement not yet resolved","How U3 release is coupled to downstream maturation steps unclear"]},{"year":2016,"claim":"Identified the cofactor that recruits and activates the helicase, answering how its activity is targeted and switched on at the preribosome.","evidence":"In vitro unwinding stimulation, co-IP, and genetic epistasis with bud23/utp14 mutants in yeast","pmids":["26729466"],"confidence":"High","gaps":["Molecular details of how Bud23 contributes to recruitment unresolved","Structural interface of the Utp14-Dhr1 complex not defined"]},{"year":2018,"claim":"Extended the U3-displacement mechanism and UTP14A cofactor relationship to human cells and linked failed recruitment to a pre-rRNA quality-control pathway.","evidence":"In vivo CRAC, catalytic-dead mutant, co-IP, and siRNA knockdown with pre-rRNA processing readout in human cells","pmids":["30582406"],"confidence":"High","gaps":["Identity of the quality-control degradation machinery not defined","Stoichiometry and timing of DHX37 recruitment in human preribosomes unclear"]},{"year":2019,"claim":"Provided structural mechanism by solving crystal structures of human DHX37 and yeast Dhr1, revealing the unique CTD required for cofactor binding and ribosome biogenesis and supporting 3'-to-5' translocation.","evidence":"X-ray crystallography with in vitro ATPase assays, mutagenesis, and in vivo rescue in both human and yeast systems","pmids":["30910870","31188444"],"confidence":"High","gaps":["No structure of the DHX37-substrate-cofactor complex on an intact preribosome","Conformational cycle during translocation not directly visualized"]},{"year":2022,"claim":"Defined the regulatory logic of the enzyme by mapping autoinhibitory N-terminal and RecA2 loop elements and showing the cofactor activates via a surface-binding mechanism distinct from G-patch activation.","evidence":"In vitro ATPase and unwinding assays with mutagenesis and yeast genetics (also refined in 2025)","pmids":["35965019","40024476"],"confidence":"Medium","gaps":["Single lab; structural snapshot of the activated state lacking","How autoinhibition is relieved in vivo not fully resolved"]},{"year":2022,"claim":"Uncovered a non-canonical chromatin function in which DHX37 partners with PLRG1 to transcriptionally activate cyclin D1 via promoter/superenhancer co-occupation, linking the helicase to oncogenic proliferation.","evidence":"Co-IP, ChIP/epigenomic profiling, and knockdown proliferation assays in hepatocellular carcinoma cells","pmids":["35290436"],"confidence":"Medium","gaps":["Whether helicase catalytic activity is required for transcriptional activation untested","Single lab; mechanism rests on co-occupancy correlation"]},{"year":2025,"claim":"Identified a genome-stability role distinct from ribosome biogenesis, showing DHX37 resolves transcription-associated R-loops to prevent replication stress.","evidence":"siRNA knockdown with γH2AX, comet, DNA fiber, RPA focus assays, RNA-DNA hybrid IF, and RNase H1 rescue in human cells","pmids":["40043837"],"confidence":"Medium","gaps":["Direct biochemical demonstration of DHX37 unwinding R-loops not shown","Genomic loci where DHX37 acts on R-loops not mapped"]},{"year":2026,"claim":"Connected DHX37 to Sertoli cell function and a nucleolar-integrity/p53 axis, showing its loss triggers FBL-MDM2-mediated p53 release and apoptosis with reproductive consequences.","evidence":"Conditional Sertoli-cell knockout mouse with snRNA-seq, RIP-seq, RNAi-RNA-seq, and biochemical readouts","pmids":["41535247"],"confidence":"Medium","gaps":["Whether the p53 phenotype is secondary to ribosome biogenesis failure not disentangled","Direct RNA targets driving the apoptotic splicing program not validated"]},{"year":2024,"claim":"Linked patient DHX37 missense variants to 46,XY disorders of sex development by showing reduced protein expression without altered localization.","evidence":"Immunofluorescence and Western blotting of a p.Arg671Thr variant in vitro","pmids":["38769888"],"confidence":"Low","gaps":["Single variant, single lab with limited functional follow-up","Mechanistic link between reduced expression and gonadal phenotype not established"]},{"year":null,"claim":"How DHX37's canonical ribosome-assembly helicase activity mechanistically relates to its R-loop resolution, transcriptional, and gonadal/apoptosis roles—and whether these share a common biochemical activity or reflect distinct interactomes—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nucleolar, chromatin, and genome-stability functions","Substrate determinants distinguishing rRNA, R-loops, and mRNA targets undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]}],"complexes":["pre-40S/small subunit processome"],"partners":["UTP14A","BUD23","PLRG1","DDX50"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IY37","full_name":"Probable ATP-dependent RNA helicase DHX37","aliases":["DEAH box protein 37"],"length_aa":1157,"mass_kda":129.5,"function":"ATP-binding RNA helicase that plays a role in maturation of the small ribosomal subunit in ribosome biogenesis (PubMed:30582406). Required for the release of the U3 snoRNP from pre-ribosomal particles (PubMed:30582406). Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome (PubMed:34516797). Plays a role in early testis development (PubMed:31287541, PubMed:31337883). Probably also plays a role in brain development (PubMed:31256877)","subcellular_location":"Nucleus, nucleolus; Cytoplasm; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q8IY37/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DHX37","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000150990","cell_line_id":"CID001106","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"PARN","stoichiometry":4.0},{"gene":"BYSL","stoichiometry":0.2},{"gene":"UTP14A","stoichiometry":0.2},{"gene":"NOP14","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS11","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP14","stoichiometry":0.2},{"gene":"TSR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001106","total_profiled":1310},"omim":[{"mim_id":"618731","title":"NEURODEVELOPMENTAL DISORDER WITH BRAIN ANOMALIES AND WITH OR WITHOUT VERTEBRAL OR CARDIAC ANOMALIES; NEDBAVC","url":"https://www.omim.org/entry/618731"},{"mim_id":"617362","title":"DEAH-BOX HELICASE 37; DHX37","url":"https://www.omim.org/entry/617362"},{"mim_id":"273250","title":"46,XY SEX REVERSAL 11; SRXY11","url":"https://www.omim.org/entry/273250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DHX37"},"hgnc":{"alias_symbol":["KIAA1517","MGC4322","MGC2695","Dhr1"],"prev_symbol":["DDX37"]},"alphafold":{"accession":"Q8IY37","domains":[{"cath_id":"3.40.50.300","chopping":"244-432","consensus_level":"high","plddt":91.5158,"start":244,"end":432},{"cath_id":"3.40.50.300","chopping":"440-494_587-692","consensus_level":"high","plddt":89.006,"start":440,"end":692},{"cath_id":"-","chopping":"779-920","consensus_level":"medium","plddt":88.306,"start":779,"end":920},{"cath_id":"-","chopping":"1059-1151","consensus_level":"medium","plddt":89.4035,"start":1059,"end":1151},{"cath_id":"2.40.50","chopping":"935-1001","consensus_level":"medium","plddt":91.2349,"start":935,"end":1001}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY37","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY37-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY37-F1-predicted_aligned_error_v6.png","plddt_mean":75.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DHX37","jax_strain_url":"https://www.jax.org/strain/search?query=DHX37"},"sequence":{"accession":"Q8IY37","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IY37.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IY37/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY37"}},"corpus_meta":[{"pmid":"25710520","id":"PMC_25710520","title":"The DEAH-box helicase Dhr1 dissociates U3 from the pre-rRNA to promote formation of the central pseudoknot.","date":"2015","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/25710520","citation_count":72,"is_preprint":false},{"pmid":"30582406","id":"PMC_30582406","title":"The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.","date":"2018","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/30582406","citation_count":56,"is_preprint":false},{"pmid":"31337883","id":"PMC_31337883","title":"Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.","date":"2019","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31337883","citation_count":50,"is_preprint":false},{"pmid":"26729466","id":"PMC_26729466","title":"Utp14 Recruits and Activates the RNA Helicase 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molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/37717579","citation_count":5,"is_preprint":false},{"pmid":"38769888","id":"PMC_38769888","title":"Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.","date":"2024","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38769888","citation_count":4,"is_preprint":false},{"pmid":"40043837","id":"PMC_40043837","title":"DDX37 and DDX50 Maintain Genome Stability by Preventing Transcription-dependent R-loop Formation.","date":"2025","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40043837","citation_count":3,"is_preprint":false},{"pmid":"40026690","id":"PMC_40026690","title":"Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development.","date":"2025","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40026690","citation_count":3,"is_preprint":false},{"pmid":"35965019","id":"PMC_35965019","title":"In vitro characterization of Dhr1 from Saccharomyces cerevisiae.","date":"2022","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/35965019","citation_count":3,"is_preprint":false},{"pmid":"40024476","id":"PMC_40024476","title":"In vitro characterization of the yeast DEAH/RHA RNA helicase Dhr1.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40024476","citation_count":3,"is_preprint":false},{"pmid":"38962685","id":"PMC_38962685","title":"Digenic Origin of Difference of Sex Development in a Patient Harbouring DHX37 and MAMLD1 Variants.","date":"2024","source":"Case reports in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38962685","citation_count":3,"is_preprint":false},{"pmid":"36598230","id":"PMC_36598230","title":"DEAD Box Protein DhR1 Is a Global Regulator Involved in the Bacterial Fitness and Virulence of Riemerella anatipestifer.","date":"2023","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/36598230","citation_count":2,"is_preprint":false},{"pmid":"40109245","id":"PMC_40109245","title":"Coexistence of SRY, DHX37 and POR gene variants in a patient with 46,XY disorder of sex development.","date":"2025","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/40109245","citation_count":2,"is_preprint":false},{"pmid":"40934457","id":"PMC_40934457","title":"Child Neurology: Clinical and Imaging Findings in a Child With DHX37 Gene Variant: A Ribosomopathy Masquerading as Cerebral Palsy.","date":"2025","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40934457","citation_count":0,"is_preprint":false},{"pmid":"41535247","id":"PMC_41535247","title":"Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41535247","citation_count":0,"is_preprint":false},{"pmid":"42057034","id":"PMC_42057034","title":"Comprehensively identifying and validating the implications of NR5A1 and DHX37 variants for 46,XY disorders of sex development diagnosis.","date":"2026","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42057034","citation_count":0,"is_preprint":false},{"pmid":"40766295","id":"PMC_40766295","title":"Case Report: De novo DHX37 mutations in Saudi patients with 46,XY differences of sex development.","date":"2025","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40766295","citation_count":0,"is_preprint":false},{"pmid":"39726663","id":"PMC_39726663","title":"An Infant With DHX37 Variant: A Novel Etiology of 46,XY DSD and Literature Review.","date":"2024","source":"JCEM case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39726663","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.10.632330","title":"Altered RNA-processing provides a mechanistic framework delineating human sex-reversal associated with pathogenic variants in the RNA-helicase DHX37","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.632330","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15328,"output_tokens":3612,"usd":0.050082,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11279,"output_tokens":3464,"usd":0.071498,"stage2_stop_reason":"end_turn"},"total_usd":0.12158,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The DEAH-box helicase Dhr1 (yeast ortholog of DHX37) is responsible for displacing U3 snoRNA from the pre-ribosome. An active-site mutant of Dhr1 blocked U3 release, trapping a pre-40S particle containing U3, pre-rRNA, and early-acting assembly factors but lacking ribosomal proteins surrounding the central pseudoknot. In vivo crosslinking showed Dhr1 contacts pre-rRNA and U3 sequences flanking regions that base-pair to form the central pseudoknot. Point mutations in the U3 box A region suppressed a cold-sensitive Dhr1 mutation, indicating U3 is an in vivo substrate. Dhr1 was also shown to unwind U3-18S duplexes in vitro.\",\n      \"method\": \"Active-site mutagenesis, in vivo crosslinking (CRAC), genetic suppressor analysis, in vitro unwinding assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (mutagenesis, crosslinking, genetic suppression, in vitro reconstitution) in a single rigorous study, independently confirmed by later work\",\n      \"pmids\": [\"25710520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Utp14 recruits and activates Dhr1 (yeast DHX37 ortholog) at the preribosome. Utp14 forms a complex with Dhr1 and directly stimulates its RNA-unwinding activity in vitro. Mutations in a discrete region of Utp14 reduced Dhr1 interaction and phenocopied a helicase-inactive Dhr1 mutant (accumulation of Dhr1 and U3 in a pre-40S particle). Stable association of Dhr1 with the preribosome requires both Utp14 and Bud23, revealing that Utp14 is bifunctional: it recruits Dhr1 (together with Bud23) and activates its unwinding activity.\",\n      \"method\": \"In vitro unwinding stimulation assay, co-immunoprecipitation, genetic epistasis with bud23 and utp14 mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical reconstitution of activation plus reciprocal genetic and interaction data, replicated in subsequent human studies\",\n      \"pmids\": [\"26729466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human DHX37 is required for maturation of the small ribosomal subunit. In vivo crosslinking showed DHX37 binds directly to U3 snoRNA, and its catalytic activity is required for dissociation of U3 snoRNA from pre-ribosomal complexes, enabling central pseudoknot formation. Failure to recruit DHX37 to early pre-ribosomal particles triggers a quality-control pathway leading to pre-rRNA degradation. UTP14A was identified as a direct interaction partner of DHX37 that acts as a cofactor stimulating helicase activity in the context of U3 snoRNA release.\",\n      \"method\": \"In vivo UV crosslinking (CRAC), catalytic-dead mutant analysis, co-immunoprecipitation, siRNA knockdown with pre-rRNA processing readout\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (crosslinking, mutagenesis, interaction mapping, knockdown phenotype) in human cells, consistent with yeast findings\",\n      \"pmids\": [\"30582406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of human DHX37 in complex with single-stranded RNA was solved, revealing a canonical DEAH ATPase/helicase architecture and a structurally unique carboxy-terminal domain (CTD). Structural comparisons with ATP-analog-bound DEAH helicases suggest ATP-dependent 3'-to-5' RNA translocation via a register shift in bound RNA. A conserved sequence motif in UTP14A directly interacts with DHX37, stimulating its ATPase activity and enhancing RNA binding. The CTD of DHX37 is required (but not sufficient) for interaction with UTP14A in vitro and is essential for ribosome biogenesis in vivo.\",\n      \"method\": \"X-ray crystallography, in vitro ATPase assay, mutagenesis, pulldown/interaction mapping\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro biochemical assays and mutagenesis of both DHX37 and UTP14A in a single rigorous study\",\n      \"pmids\": [\"30910870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The crystal structure of the yeast Dhr1 helicase module was solved, revealing a remarkable carboxy-terminal domain (CTD) essential for Dhr1 function in ribosome biogenesis in vivo and important for interaction with its coactivator Utp14 in vitro. DHX37 patient mutations (associated with microcephaly and neurological disease) mapped to this structure show functional consequences on ribosome biogenesis.\",\n      \"method\": \"X-ray crystallography, in vivo functional rescue assays, in vitro interaction assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vivo and in vitro functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31188444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Purified Dhr1 (yeast DHX37 ortholog) is an active RNA-dependent ATPase with specific RNA-unwinding activity in vitro. The N-terminus and an internal loop within the RecA2 domain are autoinhibitory elements. Utp14 can activate the ATPase activity of Dhr1 lacking the autoinhibitory N-terminal loop but not full-length Dhr1, and Utp14 activates Dhr1 by binding to the surface of the RecA1 and RecA2 domains rather than by displacing the inhibitory loop, which is distinct from G-patch protein activation of other DEXH/RHA helicases.\",\n      \"method\": \"In vitro ATPase assay, unwinding assay, mutagenesis, yeast genetics\",\n      \"journal\": \"Methods in enzymology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — detailed in vitro biochemical characterization, single lab, protocols paper but contains original data\",\n      \"pmids\": [\"35965019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dhr1 N-terminus and an internal loop within the RecA2 domain are autoinhibitory. Utp14 activates Dhr1 by binding to the surface of the RecA1 and RecA2 domains, a mechanism distinct from how G-patch proteins activate other DEXH/RHA helicases. Utp14 activates Dhr1 lacking the autoinhibitory N-terminal loop but not full-length Dhr1, suggesting Utp14 does not relieve autoinhibition by displacing the inhibitory loop.\",\n      \"method\": \"In vitro ATPase assay, unwinding assay, mutant analysis, yeast genetic complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with mutagenesis across multiple constructs, single lab\",\n      \"pmids\": [\"40024476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DHX37 interacts with PLRG1 and co-occupies the promoter and superenhancer elements of cyclin D1 (CCND1) to transcriptionally activate CCND1 expression in hepatocellular carcinoma cells, promoting cell proliferation. This represents a non-canonical function of DHX37 distinct from its role in ribosome biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), epigenomic profiling, knockdown with proliferation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ChIP-seq, and functional knockdown in a single lab; mechanistic claim rests on co-occupancy and interaction data\",\n      \"pmids\": [\"35290436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DHX37 (also annotated as DDX37) and DDX50 resolve RNA-DNA hybrids (R-loops) that form during transcription, thereby preventing replication stress and DNA damage. Depletion of DHX37 caused increased H2AX phosphorylation, increased comet tail length, decreased replication track length, and RPA focus formation. The increased RNA-DNA hybrids upon DHX37 depletion could be reversed by RNase H1 overexpression, and transcription inhibition prevented R-loop accumulation and DNA damage.\",\n      \"method\": \"siRNA knockdown, γH2AX immunofluorescence, comet assay, DNA fiber assay, RPA focus formation, RNase H1 rescue, RNA-DNA hybrid immunofluorescence\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts of R-loop and DNA damage phenotypes with RNase H1 rescue, single lab\",\n      \"pmids\": [\"40043837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an in vitro cellular model of human Sertoli cell formation, mutant DHX37 (p.R674Q) retains ATPase activity and is not associated with stabilization of cellular β-catenin. Transfection of mutant DHX37 in induced Sertoli-like cells (iSLCs) showed reduced activation of pro-testis genes compared to WT. HyperTRIBE combined with single-cell full-length RNA-sequencing revealed that WT DHX37 targets transcripts associated primarily with cytoskeleton organization, while the mutant DHX37 targets additional transcripts associated with protein degradation and cell death.\",\n      \"method\": \"ATPase activity assay, HyperTRIBE RNA-binding mapping, single-cell full-length RNA-seq, transfection in iSLCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal RNA-binding and transcriptomic methods in a human cellular model, single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632330\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cell-specific Dhx37 knockout in mouse Sertoli cells caused reduced testicular volume, lower testosterone levels, seminiferous tubule vacuolization, reduced cell proliferation, and elevated apoptosis. RIP-seq and RNAi-RNA-seq in Sertoli cells showed Dhx37 safeguards nucleolar integrity and PI3K-AKT signaling, and suppresses p53-driven apoptosis; Dhx37 loss triggers pro-apoptotic splicing. Loss of nucleolar integrity caused FBL to exit the nucleolus and bind MDM2, thereby releasing p53 to promote apoptosis.\",\n      \"method\": \"Conditional knockout mouse, immunofluorescence, single-nucleus RNA-seq, RIP-seq, RNAi-RNA-seq, Western blotting, qRT-PCR\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple cellular phenotype readouts and mechanistic RNA-seq, single lab\",\n      \"pmids\": [\"41535247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel pathogenic DHX37 variant (p.Arg671Thr) found in a 46,XY DSD patient had no significant effect on intracellular localization of the DHX37 protein but significantly reduced its expression level in vitro, as assessed by immunofluorescence and Western blotting.\",\n      \"method\": \"Immunofluorescence (subcellular localization), Western blotting (protein level)\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single variant, single lab, limited functional follow-up beyond localization and expression level\",\n      \"pmids\": [\"38769888\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DHX37 (Dhr1 in yeast) is a DEAH-box RNA helicase that uses ATP-dependent 3'-to-5' translocation—revealed by its crystal structure—to unwind and displace U3 snoRNA from pre-ribosomal particles, enabling central pseudoknot formation and small ribosomal subunit maturation; its activity is regulated by autoinhibitory elements in the N-terminus and RecA2 loop, and is stimulated by its cofactor UTP14A, which binds the RecA1/RecA2 surface and enhances ATPase activity and RNA binding; additionally, DHX37 resolves transcription-associated R-loops to prevent replication stress, and in certain cancer contexts cooperates with PLRG1 to transcriptionally activate cyclin D1 via superenhancer co-occupation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHX37 (yeast Dhr1) is a DEAH-box RNA helicase that catalyzes a key remodeling step in small ribosomal subunit biogenesis by ATP-dependently displacing U3 snoRNA from pre-ribosomal particles, thereby licensing formation of the central pseudoknot of the 18S rRNA [#0, #2]. Its crystal structure reveals a canonical DEAH ATPase/helicase core plus a structurally distinct carboxy-terminal domain that supports 3'-to-5' RNA translocation, is essential for ribosome biogenesis in vivo, and mediates interaction with its cofactor [#3, #4]. DHX37 activity is held in check by autoinhibitory elements\\u2014its N-terminus and an internal RecA2 loop\\u2014and is stimulated by UTP14A/Utp14, which binds the RecA1/RecA2 surface to enhance ATPase and RNA-unwinding activity and, together with Bud23, recruits the helicase to the preribosome; this activation mode is distinct from G-patch protein activation of other DEXH/RHA helicases [#1, #3, #5, #6]. Beyond ribosome assembly, DHX37 resolves transcription-associated RNA-DNA hybrids (R-loops) to prevent replication stress and DNA damage, a function confirmed by RNase H1 rescue and transcription inhibition [#8], and it cooperates with PLRG1 to co-occupy the CCND1 promoter and superenhancer and transcriptionally activate cyclin D1 in hepatocellular carcinoma [#7]. In Sertoli cells, DHX37 safeguards nucleolar integrity and suppresses p53-driven apoptosis, with its loss causing FBL to exit the nucleolus, bind MDM2, and release p53; patient-derived missense variants associated with 46,XY disorders of sex development impair DHX37 function or expression [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the core enzymatic function of the helicase by identifying U3 snoRNA as its physiological substrate during ribosome assembly, answering what reaction this helicase performs at the preribosome.\",\n      \"evidence\": \"Active-site mutagenesis, in vivo CRAC crosslinking, genetic suppressor analysis, and in vitro unwinding assays in yeast Dhr1\",\n      \"pmids\": [\"25710520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of U3 engagement not yet resolved\", \"How U3 release is coupled to downstream maturation steps unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the cofactor that recruits and activates the helicase, answering how its activity is targeted and switched on at the preribosome.\",\n      \"evidence\": \"In vitro unwinding stimulation, co-IP, and genetic epistasis with bud23/utp14 mutants in yeast\",\n      \"pmids\": [\"26729466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of how Bud23 contributes to recruitment unresolved\", \"Structural interface of the Utp14-Dhr1 complex not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the U3-displacement mechanism and UTP14A cofactor relationship to human cells and linked failed recruitment to a pre-rRNA quality-control pathway.\",\n      \"evidence\": \"In vivo CRAC, catalytic-dead mutant, co-IP, and siRNA knockdown with pre-rRNA processing readout in human cells\",\n      \"pmids\": [\"30582406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the quality-control degradation machinery not defined\", \"Stoichiometry and timing of DHX37 recruitment in human preribosomes unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided structural mechanism by solving crystal structures of human DHX37 and yeast Dhr1, revealing the unique CTD required for cofactor binding and ribosome biogenesis and supporting 3'-to-5' translocation.\",\n      \"evidence\": \"X-ray crystallography with in vitro ATPase assays, mutagenesis, and in vivo rescue in both human and yeast systems\",\n      \"pmids\": [\"30910870\", \"31188444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the DHX37-substrate-cofactor complex on an intact preribosome\", \"Conformational cycle during translocation not directly visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the regulatory logic of the enzyme by mapping autoinhibitory N-terminal and RecA2 loop elements and showing the cofactor activates via a surface-binding mechanism distinct from G-patch activation.\",\n      \"evidence\": \"In vitro ATPase and unwinding assays with mutagenesis and yeast genetics (also refined in 2025)\",\n      \"pmids\": [\"35965019\", \"40024476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural snapshot of the activated state lacking\", \"How autoinhibition is relieved in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a non-canonical chromatin function in which DHX37 partners with PLRG1 to transcriptionally activate cyclin D1 via promoter/superenhancer co-occupation, linking the helicase to oncogenic proliferation.\",\n      \"evidence\": \"Co-IP, ChIP/epigenomic profiling, and knockdown proliferation assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"35290436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether helicase catalytic activity is required for transcriptional activation untested\", \"Single lab; mechanism rests on co-occupancy correlation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a genome-stability role distinct from ribosome biogenesis, showing DHX37 resolves transcription-associated R-loops to prevent replication stress.\",\n      \"evidence\": \"siRNA knockdown with \\u03b3H2AX, comet, DNA fiber, RPA focus assays, RNA-DNA hybrid IF, and RNase H1 rescue in human cells\",\n      \"pmids\": [\"40043837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration of DHX37 unwinding R-loops not shown\", \"Genomic loci where DHX37 acts on R-loops not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected DHX37 to Sertoli cell function and a nucleolar-integrity/p53 axis, showing its loss triggers FBL-MDM2-mediated p53 release and apoptosis with reproductive consequences.\",\n      \"evidence\": \"Conditional Sertoli-cell knockout mouse with snRNA-seq, RIP-seq, RNAi-RNA-seq, and biochemical readouts\",\n      \"pmids\": [\"41535247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the p53 phenotype is secondary to ribosome biogenesis failure not disentangled\", \"Direct RNA targets driving the apoptotic splicing program not validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked patient DHX37 missense variants to 46,XY disorders of sex development by showing reduced protein expression without altered localization.\",\n      \"evidence\": \"Immunofluorescence and Western blotting of a p.Arg671Thr variant in vitro\",\n      \"pmids\": [\"38769888\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single variant, single lab with limited functional follow-up\", \"Mechanistic link between reduced expression and gonadal phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DHX37's canonical ribosome-assembly helicase activity mechanistically relates to its R-loop resolution, transcriptional, and gonadal/apoptosis roles\\u2014and whether these share a common biochemical activity or reflect distinct interactomes\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nucleolar, chromatin, and genome-stability functions\", \"Substrate determinants distinguishing rRNA, R-loops, and mRNA targets undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"pre-40S/small subunit processome\"],\n    \"partners\": [\"UTP14A\", \"BUD23\", \"PLRG1\", \"DDX50\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}