{"gene":"SKIC2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1998,"finding":"SKI2 is required for the 3' to 5' decay pathway of mRNA in yeast. Genetic experiments showed that ski2 mutants block 3' to 5' degradation of mRNA, and that SKI2 acts together with SKI3, SKI8, and exosome components (SKI6/RRP41, RRP4) to degrade mRNA bodies in a 3' to 5' direction. Blocking both 3' to 5' and 5' to 3' decay pathways simultaneously causes inviability with extremely long mRNA half-lives.","method":"Genetic epistasis with ski2/ski3/ski6/ski8/rrp4 mutants; mRNA half-life measurements; synthetic lethality with 5'-3' decay mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across multiple mutants, replicated findings with multiple gene knockouts, foundational study replicated by subsequent work","pmids":["9482746"],"is_preprint":false},{"year":1995,"finding":"sep1/xrn1 ski2 double mutants of S. cerevisiae are synthetically lethal independently of the killer virus (L-A and M dsRNA viruses), demonstrating that SKI2 performs a general cellular function beyond antiviral activity, proposed to involve blocking translation on transcripts targeted for degradation. The double mutants also show a synthetic cell cycle arrest in late G1 at Start.","method":"Genetic synthetic lethality screen; double-mutant analysis; virus-cured strains; temperature-sensitive alleles","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with clear phenotypic readouts, single lab, mechanistic interpretation proposed but not fully demonstrated biochemically","pmids":["7739552"],"is_preprint":false},{"year":1995,"finding":"The human SKI2W (SKIC2) protein contains consensus sequences for an RNA helicase with a DEVH box and has ATPase activity when expressed as a fusion protein in insect cells using a baculovirus vector.","method":"Sequence analysis; baculovirus expression; ATPase activity assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay demonstrating ATPase activity, single lab, single method","pmids":["7610041"],"is_preprint":false},{"year":1998,"finding":"Human Ski2w (SKIC2) protein is enriched in polysomal fractions of cytoplasmic extracts from HeLa cells and co-sediments with the 40S ribosomal subunit in the presence of EDTA. This association is resistant to RNase A treatment and 0.5 M KCl, indicating direct protein-protein contact with the 40S subunit. By indirect immunofluorescence, Ski2w is localized in nucleoli and cytoplasm.","method":"Sucrose gradient sedimentation; co-sedimentation with 18S rRNA and S27a protein; RNase A and high-salt resistance assay; indirect immunofluorescence","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sedimentation, co-sedimentation, RNase/salt resistance, immunofluorescence) in single lab","pmids":["9705521"],"is_preprint":false},{"year":2005,"finding":"Within the yeast Ski2-Ski3-Ski8 complex, Ski3p serves as a scaffold: its C-terminus interacts with Ski8p and its sub-C-terminus interacts with Ski2p, while no direct interaction between Ski2p and Ski8p was detected. Ski7p interacts with the Ski complex via Ski8p and Ski3p. Mutating conserved DEVH helicase motif residues in Ski2p abolishes its enzymatic activity but does not disrupt its interaction with Ski7p, indicating helicase activity is dispensable for complex assembly.","method":"Directed yeast two-hybrid; co-immunoprecipitation; in vivo functional assays with helicase-dead Ski2p mutants","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP combined with two-hybrid and in vivo functional assays, multiple interaction pairs tested, helicase-dead mutagenesis","pmids":["16043509"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the 113 kDa helicase region of S. cerevisiae Ski2 at 2.4 Å resolution reveals an overall architecture similar to Mtr4, with a core DExH region and an extended insertion domain. The insertion domain is not required for Ski2-Ski3-Ski8 complex formation but instead functions as an RNA-binding domain with broad substrate specificity, binding both single-stranded and double-stranded RNAs. A zinc-binding site maintains the β-barrel and helical stalk as a single structural unit. The β-barrel lacks a KOW motif (unlike Mtr4).","method":"X-ray crystallography at 2.4 Å; in vitro RNA-binding assays; deletion constructs for complex formation","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical RNA-binding assays and deletion analysis, rigorous structural validation","pmids":["22114319"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structure of an endogenous ribosome-Ski2-Ski3-Ski8 complex shows that the Ski complex directly associates with 80S ribosomes presenting a short mRNA 3' overhang. Ribosome binding displaces the autoinhibitory domain of Ski2, positioning it in an open conformation near the ribosomal mRNA entry tunnel. The mRNA 3' overhang is threaded directly from the small ribosomal subunit into the helicase channel of Ski2, primed for exosome-mediated 3'-5' degradation.","method":"Cryo-electron microscopy of endogenous complex; structural analysis at 4 Å (core) to ~10 Å (flexible regions)","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of endogenous complex at near-atomic resolution with functional mechanistic interpretation of autoinhibitory domain displacement and mRNA threading","pmids":["27980209"],"is_preprint":false},{"year":2018,"finding":"Human Ski2 (SKIC2) and the RNA exosome complex mediate degradation of HBV HBx mRNA. IL-1β induces expression of ATF3 transcription factor, which binds to a CRE sequence in the Ski2 promoter and drives Ski2 transcription, leading to increased HBx mRNA degradation. HBx protein itself also induces Ski2 expression.","method":"Promoter-reporter assays; ChIP for ATF3 binding to Ski2 promoter; siRNA knockdown; mRNA stability assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter analysis, ChIP, and functional mRNA degradation assays, single lab","pmids":["30055801"],"is_preprint":false}],"current_model":"SKIC2 (SKI2/SKI2W/SKIV2L/DDX13) is a DExH-box RNA helicase that forms the Ski2-Ski3-Ski8 (SKI) complex — where Ski3 acts as scaffold bridging Ski2 and Ski8 — and functions as a cytoplasmic cofactor of the RNA-degrading exosome to mediate 3'-5' mRNA decay in both general turnover and quality-control pathways; cryo-EM structural data show that the SKI complex docks directly onto 80S ribosomes presenting a 3' mRNA overhang, with ribosome binding displacing the autoinhibitory domain of Ski2 and threading the mRNA directly into the Ski2 helicase channel for exosome-mediated degradation, while the human ortholog localizes to nucleoli and cytoplasm and associates with the 40S ribosomal subunit."},"narrative":{"mechanistic_narrative":"SKIC2 (SKI2/SKI2W/SKIV2L) is a DExH-box RNA helicase that drives cytoplasmic 3'-to-5' mRNA decay as the catalytic engine of the Ski2-Ski3-Ski8 (SKI) complex, acting together with the RNA exosome in both general mRNA turnover and quality control [PMID:9482746]. The protein carries a DEVH-box helicase signature and possesses intrinsic ATPase activity [PMID:7610041]. Within the complex, Ski3 functions as a scaffold whose C-terminus binds Ski8 and whose sub-C-terminal region binds Ski2, with no direct Ski2-Ski8 contact; the helicase activity of Ski2 is dispensable for complex assembly, since helicase-dead mutants still associate with Ski7 [PMID:16043509]. Structurally, the Ski2 helicase region adopts an Mtr4-like architecture with an extended insertion domain that serves as a broad-specificity RNA-binding module rather than a complex-assembly element [PMID:22114319]. Mechanistically, the SKI complex docks directly onto 80S ribosomes presenting a short 3' mRNA overhang; ribosome binding displaces the autoinhibitory domain of Ski2 into an open conformation near the mRNA entry tunnel and threads the 3' overhang from the small subunit directly into the Ski2 helicase channel, priming it for exosome-mediated degradation [PMID:27980209]. The human ortholog co-sediments with the 40S ribosomal subunit through salt- and RNase-resistant contacts and localizes to nucleoli and cytoplasm [PMID:9705521]. Beyond core decay, human SKIC2 with the exosome degrades hepatitis B HBx mRNA, and its transcription is induced via IL-1β/ATF3 signaling acting on a CRE element in the SKIC2 promoter [PMID:30055801].","teleology":[{"year":1995,"claim":"Establishing that SKI2 has a general cellular role beyond antiviral defense was the first step in recognizing it as a core mRNA decay factor rather than a virus-specific repressor.","evidence":"Genetic synthetic lethality of sep1/xrn1 ski2 double mutants in virus-cured yeast strains with cell cycle arrest at Start","pmids":["7739552"],"confidence":"Medium","gaps":["The molecular basis of the general function was inferred genetically, not demonstrated biochemically","Did not directly link SKI2 to the 3'-5' decay machinery"]},{"year":1995,"claim":"Identifying the human SKI2W ortholog as a DEVH-box helicase with ATPase activity defined the enzyme's catalytic identity.","evidence":"Sequence analysis plus baculovirus expression and in vitro ATPase assay of the fusion protein","pmids":["7610041"],"confidence":"Medium","gaps":["ATPase shown for a fusion protein in vitro; helicase (duplex unwinding) activity not directly demonstrated","No substrate specificity defined"]},{"year":1998,"claim":"Placing SKI2 within the 3'-5' decay pathway alongside exosome components defined its pathway membership and showed it is essential when combined with loss of 5'-3' decay.","evidence":"Genetic epistasis with ski3/ski6/ski8/rrp4 mutants, mRNA half-life measurements, and synthetic lethality with 5'-3' decay mutants in yeast","pmids":["9482746"],"confidence":"High","gaps":["Did not resolve physical organization of the SKI complex","Direct biochemical coupling to the exosome not yet shown"]},{"year":1998,"claim":"Demonstrating physical association of human Ski2w with the 40S ribosomal subunit and its nucleolar/cytoplasmic localization connected the helicase to translating ribosomes.","evidence":"Sucrose gradient sedimentation, RNase A/high-salt-resistant co-sedimentation with 18S rRNA and S27a, and indirect immunofluorescence in HeLa cells","pmids":["9705521"],"confidence":"Medium","gaps":["Functional consequence of 40S association not established","Nucleolar localization role uncharacterized"]},{"year":2005,"claim":"Defining the architecture of the SKI complex established Ski3 as the scaffold and showed helicase catalysis is separable from complex assembly.","evidence":"Directed yeast two-hybrid, reciprocal co-immunoprecipitation, and in vivo assays with helicase-dead Ski2p mutants","pmids":["16043509"],"confidence":"High","gaps":["Stoichiometry and quantitative affinities not determined","Structural basis of the interactions not resolved"]},{"year":2011,"claim":"The crystal structure of the Ski2 helicase region defined its Mtr4-like fold and identified the insertion domain as a broad-specificity RNA-binding module.","evidence":"X-ray crystallography at 2.4 Å with in vitro RNA-binding and deletion-construct assays","pmids":["22114319"],"confidence":"High","gaps":["Structure of full-length protein and assembled complex not captured","Mechanism of substrate channeling not shown"]},{"year":2016,"claim":"The cryo-EM ribosome-SKI structure resolved the central mechanistic question of how the complex extracts mRNA for decay, showing direct ribosome docking, autoinhibition relief, and 3'-overhang threading into the helicase channel.","evidence":"Cryo-EM of an endogenous 80S ribosome-Ski2-Ski3-Ski8 complex at ~4 Å core resolution","pmids":["27980209"],"confidence":"High","gaps":["Direct handoff to the exosome not captured structurally","Dynamics of mRNA translocation through the channel not resolved"]},{"year":2018,"claim":"Linking human SKIC2/exosome activity to viral HBx mRNA decay and to IL-1β/ATF3 transcriptional induction connected the decay machinery to inducible antiviral gene regulation.","evidence":"Promoter-reporter assays, ChIP for ATF3 binding, siRNA knockdown, and mRNA stability assays","pmids":["30055801"],"confidence":"Medium","gaps":["Single-lab study; direct helicase action on HBx mRNA not structurally resolved","Breadth of viral/cellular targets regulated this way unknown"]},{"year":null,"claim":"How the human SKI complex physically hands threaded mRNA to the exosome, and the functional role of SKIC2 nucleolar localization, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the human SKI-exosome-ribosome supercomplex","Nucleolar function of human SKIC2 uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6]}],"complexes":["SKI complex (Ski2-Ski3-Ski8)"],"partners":["SKIC3","SKIC8","SKI7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15477","full_name":"Superkiller complex protein 2","aliases":["Helicase-like protein","HLP"],"length_aa":1246,"mass_kda":137.8,"function":"Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways (PubMed:16024656, PubMed:32006463, PubMed:35120588). The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation (PubMed:32006463, PubMed:35120588). SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling (PubMed:32006463). In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C) (PubMed:16024656). May play a role in the non-stop mRNA decay pathway (NSD), which specifically targets and degrades mRNAs that lack a proper stop codon (PubMed:40441874)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15477/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SKIC2","classification":"Not Classified","n_dependent_lines":106,"n_total_lines":1208,"dependency_fraction":0.08774834437086093},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"EIF2S3","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP72","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SKIC2","total_profiled":1310},"omim":[{"mim_id":"619991","title":"LIVER DISEASE, SEVERE CONGENITAL; SCOLIV","url":"https://www.omim.org/entry/619991"},{"mim_id":"614606","title":"FOCADHESIN; FOCAD","url":"https://www.omim.org/entry/614606"},{"mim_id":"614602","title":"TRICHOHEPATOENTERIC SYNDROME 2; THES2","url":"https://www.omim.org/entry/614602"},{"mim_id":"600478","title":"SKI2 SUBUNIT OF SUPERKILLER COMPLEX; SKIC2","url":"https://www.omim.org/entry/600478"},{"mim_id":"222470","title":"TRICHOHEPATOENTERIC SYNDROME 1; THES1","url":"https://www.omim.org/entry/222470"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SKIC2"},"hgnc":{"alias_symbol":["HLP","DDX13","SKI2W","170A","SKIV2L1","SKI2"],"prev_symbol":["SKIV2","SKIV2L"]},"alphafold":{"accession":"Q15477","domains":[{"cath_id":"3.40.50.300","chopping":"283-479","consensus_level":"high","plddt":90.6162,"start":283,"end":479},{"cath_id":"-","chopping":"807-879_900-1012","consensus_level":"high","plddt":85.5525,"start":807,"end":1012},{"cath_id":"1.10.3380.30","chopping":"1084-1232","consensus_level":"high","plddt":89.8043,"start":1084,"end":1232},{"cath_id":"1.10.287","chopping":"772-799_1020-1049","consensus_level":"medium","plddt":89.3016,"start":772,"end":1049}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15477","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15477-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15477-F1-predicted_aligned_error_v6.png","plddt_mean":80.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKIC2","jax_strain_url":"https://www.jax.org/strain/search?query=SKIC2"},"sequence":{"accession":"Q15477","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15477.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15477/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15477"}},"corpus_meta":[{"pmid":"9482746","id":"PMC_9482746","title":"The 3' to 5' degradation of yeast mRNAs is a general mechanism for mRNA turnover that requires the SKI2 DEVH box protein and 3' to 5' exonucleases of the exosome complex.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9482746","citation_count":545,"is_preprint":false},{"pmid":"27980209","id":"PMC_27980209","title":"The cryo-EM structure of a ribosome-Ski2-Ski3-Ski8 helicase complex.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27980209","citation_count":95,"is_preprint":false},{"pmid":"7739552","id":"PMC_7739552","title":"Synthetic lethality of sep1 (xrn1) ski2 and sep1 (xrn1) ski3 mutants of Saccharomyces cerevisiae is independent of killer virus and suggests a general role for these genes in translation control.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7739552","citation_count":82,"is_preprint":false},{"pmid":"22995828","id":"PMC_22995828","title":"Ski2-like RNA helicase structures: common themes and complex assemblies.","date":"2012","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/22995828","citation_count":72,"is_preprint":false},{"pmid":"22114319","id":"PMC_22114319","title":"The crystal structure of S. cerevisiae Ski2, a DExH helicase associated with the cytoplasmic functions of the exosome.","date":"2011","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22114319","citation_count":64,"is_preprint":false},{"pmid":"7610041","id":"PMC_7610041","title":"Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7610041","citation_count":50,"is_preprint":false},{"pmid":"16043509","id":"PMC_16043509","title":"Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p.","date":"2005","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16043509","citation_count":48,"is_preprint":false},{"pmid":"9705521","id":"PMC_9705521","title":"The human DEVH-box protein Ski2w from the HLA is localized in nucleoli and ribosomes.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9705521","citation_count":35,"is_preprint":false},{"pmid":"7759100","id":"PMC_7759100","title":"Identification and characterization of a human cDNA homologous to yeast SKI2.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7759100","citation_count":34,"is_preprint":false},{"pmid":"9799600","id":"PMC_9799600","title":"Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9799600","citation_count":28,"is_preprint":false},{"pmid":"32030412","id":"PMC_32030412","title":"RNA processing machineries in Archaea: the 5'-3' exoribonuclease aRNase J of the β-CASP family is engaged specifically with the helicase ASH-Ski2 and the 3'-5' exoribonucleolytic RNA exosome machinery.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32030412","citation_count":20,"is_preprint":false},{"pmid":"31859026","id":"PMC_31859026","title":"Molecular Mechanism Underlying Inhibition of Intrinsic ATPase Activity in a Ski2-like RNA Helicase.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31859026","citation_count":15,"is_preprint":false},{"pmid":"9133744","id":"PMC_9133744","title":"Identification of gene encoding a putative RNA-helicase, homologous to SKI2, in chromosome VII of Saccharomyces cerevisiae.","date":"1997","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9133744","citation_count":15,"is_preprint":false},{"pmid":"30055801","id":"PMC_30055801","title":"IL-1β/ATF3-mediated induction of Ski2 expression enhances hepatitis B virus x mRNA degradation.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30055801","citation_count":13,"is_preprint":false},{"pmid":"11472843","id":"PMC_11472843","title":"The Drosophila gene twister, an orthologue of the yeast helicase SKI2, is differentially expressed during development.","date":"2001","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11472843","citation_count":11,"is_preprint":false},{"pmid":"10774746","id":"PMC_10774746","title":"Identification and characterization of a bidirectional promoter from the intergenic region between the human DDX13 and RD genes.","date":"2000","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/10774746","citation_count":10,"is_preprint":false},{"pmid":"11487501","id":"PMC_11487501","title":"Features of the two gene pairs RD-SKI2W and DOM3Z-RP1 located between complement component genes factor B and C4 at the MHC class III region.","date":"2001","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/11487501","citation_count":9,"is_preprint":false},{"pmid":"38517341","id":"PMC_38517341","title":"Tracing Allostery in the Spliceosome Ski2-like RNA Helicase Brr2.","date":"2024","source":"The journal of physical chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/38517341","citation_count":8,"is_preprint":false},{"pmid":"26644515","id":"PMC_26644515","title":"The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26644515","citation_count":5,"is_preprint":false},{"pmid":"38500564","id":"PMC_38500564","title":"Evolutionary and functional insights into the Ski2-like helicase family in Archaea: a comparison of Thermococcales ASH-Ski2 and Hel308 activities.","date":"2024","source":"NAR genomics and bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/38500564","citation_count":4,"is_preprint":false},{"pmid":"36240494","id":"PMC_36240494","title":"The RNA helicase Ski2 in the fungal pathogen Cryptococcus neoformans highlights key roles in azoles resistance and stress tolerance.","date":"2022","source":"Medical mycology","url":"https://pubmed.ncbi.nlm.nih.gov/36240494","citation_count":4,"is_preprint":false},{"pmid":"9264031","id":"PMC_9264031","title":"Genomic organization of the human DDX13 gene located between RD and RP1 in the class III MHC complex.","date":"1997","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/9264031","citation_count":4,"is_preprint":false},{"pmid":"34048711","id":"PMC_34048711","title":"Long-range allostery mediates cooperative adenine nucleotide binding by the Ski2-like RNA helicase Brr2.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34048711","citation_count":3,"is_preprint":false},{"pmid":"41785087","id":"PMC_41785087","title":"Ski2-like helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41785087","citation_count":1,"is_preprint":false},{"pmid":"40777259","id":"PMC_40777259","title":"The Ski2 helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40777259","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12813,"output_tokens":2722,"usd":0.039635,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9454,"output_tokens":2971,"usd":0.060773,"stage2_stop_reason":"end_turn"},"total_usd":0.100408,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the papers, I need to identify which ones are about SKIC2 (also known as SKIV2L, SKI2W, DDX13, etc.) versus papers about related but distinct proteins (like Brr2, ASCC3, or archaeal/Drosophila/fungal orthologs).\n\n- Papers 1-10, 14, 16-17: About SKIC2/SKI2/SKI2W/DDX13 directly\n- Papers 11, 20: Archaeal Ski2-like helicases - functionally incompatible context, likely symbol collision\n- Paper 12, 18, 23: About Brr2, a different Ski2-like helicase family member - NOT SKIC2\n- Paper 13: S. cerevisiae gene homologous to SKI2 but a different gene (G9365 on chr VII)\n- Paper 15: Drosophila twister, ortholog of SKI2 - include as ortholog study\n- Paper 19: Drosophila Obelus, a Ski2-family helicase - but described as regulating splicing, which is inconsistent with SKIC2's known mRNA decay role; likely a different paralog\n- Papers 21: Cryptococcus Ski2 - ortholog\n- Papers 24, 25: ASCC3, a different human Ski2-like helicase - NOT SKIC2\n- Paper 2, 5: Yeast Ski2 crystal/cryo-EM structures - these are direct orthologs, include\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SKI2 is required for the 3' to 5' decay pathway of mRNA in yeast. Genetic experiments showed that ski2 mutants block 3' to 5' degradation of mRNA, and that SKI2 acts together with SKI3, SKI8, and exosome components (SKI6/RRP41, RRP4) to degrade mRNA bodies in a 3' to 5' direction. Blocking both 3' to 5' and 5' to 3' decay pathways simultaneously causes inviability with extremely long mRNA half-lives.\",\n      \"method\": \"Genetic epistasis with ski2/ski3/ski6/ski8/rrp4 mutants; mRNA half-life measurements; synthetic lethality with 5'-3' decay mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across multiple mutants, replicated findings with multiple gene knockouts, foundational study replicated by subsequent work\",\n      \"pmids\": [\"9482746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"sep1/xrn1 ski2 double mutants of S. cerevisiae are synthetically lethal independently of the killer virus (L-A and M dsRNA viruses), demonstrating that SKI2 performs a general cellular function beyond antiviral activity, proposed to involve blocking translation on transcripts targeted for degradation. The double mutants also show a synthetic cell cycle arrest in late G1 at Start.\",\n      \"method\": \"Genetic synthetic lethality screen; double-mutant analysis; virus-cured strains; temperature-sensitive alleles\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with clear phenotypic readouts, single lab, mechanistic interpretation proposed but not fully demonstrated biochemically\",\n      \"pmids\": [\"7739552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human SKI2W (SKIC2) protein contains consensus sequences for an RNA helicase with a DEVH box and has ATPase activity when expressed as a fusion protein in insect cells using a baculovirus vector.\",\n      \"method\": \"Sequence analysis; baculovirus expression; ATPase activity assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay demonstrating ATPase activity, single lab, single method\",\n      \"pmids\": [\"7610041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human Ski2w (SKIC2) protein is enriched in polysomal fractions of cytoplasmic extracts from HeLa cells and co-sediments with the 40S ribosomal subunit in the presence of EDTA. This association is resistant to RNase A treatment and 0.5 M KCl, indicating direct protein-protein contact with the 40S subunit. By indirect immunofluorescence, Ski2w is localized in nucleoli and cytoplasm.\",\n      \"method\": \"Sucrose gradient sedimentation; co-sedimentation with 18S rRNA and S27a protein; RNase A and high-salt resistance assay; indirect immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sedimentation, co-sedimentation, RNase/salt resistance, immunofluorescence) in single lab\",\n      \"pmids\": [\"9705521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Within the yeast Ski2-Ski3-Ski8 complex, Ski3p serves as a scaffold: its C-terminus interacts with Ski8p and its sub-C-terminus interacts with Ski2p, while no direct interaction between Ski2p and Ski8p was detected. Ski7p interacts with the Ski complex via Ski8p and Ski3p. Mutating conserved DEVH helicase motif residues in Ski2p abolishes its enzymatic activity but does not disrupt its interaction with Ski7p, indicating helicase activity is dispensable for complex assembly.\",\n      \"method\": \"Directed yeast two-hybrid; co-immunoprecipitation; in vivo functional assays with helicase-dead Ski2p mutants\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP combined with two-hybrid and in vivo functional assays, multiple interaction pairs tested, helicase-dead mutagenesis\",\n      \"pmids\": [\"16043509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the 113 kDa helicase region of S. cerevisiae Ski2 at 2.4 Å resolution reveals an overall architecture similar to Mtr4, with a core DExH region and an extended insertion domain. The insertion domain is not required for Ski2-Ski3-Ski8 complex formation but instead functions as an RNA-binding domain with broad substrate specificity, binding both single-stranded and double-stranded RNAs. A zinc-binding site maintains the β-barrel and helical stalk as a single structural unit. The β-barrel lacks a KOW motif (unlike Mtr4).\",\n      \"method\": \"X-ray crystallography at 2.4 Å; in vitro RNA-binding assays; deletion constructs for complex formation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical RNA-binding assays and deletion analysis, rigorous structural validation\",\n      \"pmids\": [\"22114319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structure of an endogenous ribosome-Ski2-Ski3-Ski8 complex shows that the Ski complex directly associates with 80S ribosomes presenting a short mRNA 3' overhang. Ribosome binding displaces the autoinhibitory domain of Ski2, positioning it in an open conformation near the ribosomal mRNA entry tunnel. The mRNA 3' overhang is threaded directly from the small ribosomal subunit into the helicase channel of Ski2, primed for exosome-mediated 3'-5' degradation.\",\n      \"method\": \"Cryo-electron microscopy of endogenous complex; structural analysis at 4 Å (core) to ~10 Å (flexible regions)\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of endogenous complex at near-atomic resolution with functional mechanistic interpretation of autoinhibitory domain displacement and mRNA threading\",\n      \"pmids\": [\"27980209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human Ski2 (SKIC2) and the RNA exosome complex mediate degradation of HBV HBx mRNA. IL-1β induces expression of ATF3 transcription factor, which binds to a CRE sequence in the Ski2 promoter and drives Ski2 transcription, leading to increased HBx mRNA degradation. HBx protein itself also induces Ski2 expression.\",\n      \"method\": \"Promoter-reporter assays; ChIP for ATF3 binding to Ski2 promoter; siRNA knockdown; mRNA stability assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter analysis, ChIP, and functional mRNA degradation assays, single lab\",\n      \"pmids\": [\"30055801\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKIC2 (SKI2/SKI2W/SKIV2L/DDX13) is a DExH-box RNA helicase that forms the Ski2-Ski3-Ski8 (SKI) complex — where Ski3 acts as scaffold bridging Ski2 and Ski8 — and functions as a cytoplasmic cofactor of the RNA-degrading exosome to mediate 3'-5' mRNA decay in both general turnover and quality-control pathways; cryo-EM structural data show that the SKI complex docks directly onto 80S ribosomes presenting a 3' mRNA overhang, with ribosome binding displacing the autoinhibitory domain of Ski2 and threading the mRNA directly into the Ski2 helicase channel for exosome-mediated degradation, while the human ortholog localizes to nucleoli and cytoplasm and associates with the 40S ribosomal subunit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKIC2 (SKI2/SKI2W/SKIV2L) is a DExH-box RNA helicase that drives cytoplasmic 3'-to-5' mRNA decay as the catalytic engine of the Ski2-Ski3-Ski8 (SKI) complex, acting together with the RNA exosome in both general mRNA turnover and quality control [#0]. The protein carries a DEVH-box helicase signature and possesses intrinsic ATPase activity [#2]. Within the complex, Ski3 functions as a scaffold whose C-terminus binds Ski8 and whose sub-C-terminal region binds Ski2, with no direct Ski2-Ski8 contact; the helicase activity of Ski2 is dispensable for complex assembly, since helicase-dead mutants still associate with Ski7 [#4]. Structurally, the Ski2 helicase region adopts an Mtr4-like architecture with an extended insertion domain that serves as a broad-specificity RNA-binding module rather than a complex-assembly element [#5]. Mechanistically, the SKI complex docks directly onto 80S ribosomes presenting a short 3' mRNA overhang; ribosome binding displaces the autoinhibitory domain of Ski2 into an open conformation near the mRNA entry tunnel and threads the 3' overhang from the small subunit directly into the Ski2 helicase channel, priming it for exosome-mediated degradation [#6]. The human ortholog co-sediments with the 40S ribosomal subunit through salt- and RNase-resistant contacts and localizes to nucleoli and cytoplasm [#3]. Beyond core decay, human SKIC2 with the exosome degrades hepatitis B HBx mRNA, and its transcription is induced via IL-1\\u03b2/ATF3 signaling acting on a CRE element in the SKIC2 promoter [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that SKI2 has a general cellular role beyond antiviral defense was the first step in recognizing it as a core mRNA decay factor rather than a virus-specific repressor.\",\n      \"evidence\": \"Genetic synthetic lethality of sep1/xrn1 ski2 double mutants in virus-cured yeast strains with cell cycle arrest at Start\",\n      \"pmids\": [\"7739552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular basis of the general function was inferred genetically, not demonstrated biochemically\", \"Did not directly link SKI2 to the 3'-5' decay machinery\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying the human SKI2W ortholog as a DEVH-box helicase with ATPase activity defined the enzyme's catalytic identity.\",\n      \"evidence\": \"Sequence analysis plus baculovirus expression and in vitro ATPase assay of the fusion protein\",\n      \"pmids\": [\"7610041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ATPase shown for a fusion protein in vitro; helicase (duplex unwinding) activity not directly demonstrated\", \"No substrate specificity defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Placing SKI2 within the 3'-5' decay pathway alongside exosome components defined its pathway membership and showed it is essential when combined with loss of 5'-3' decay.\",\n      \"evidence\": \"Genetic epistasis with ski3/ski6/ski8/rrp4 mutants, mRNA half-life measurements, and synthetic lethality with 5'-3' decay mutants in yeast\",\n      \"pmids\": [\"9482746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve physical organization of the SKI complex\", \"Direct biochemical coupling to the exosome not yet shown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating physical association of human Ski2w with the 40S ribosomal subunit and its nucleolar/cytoplasmic localization connected the helicase to translating ribosomes.\",\n      \"evidence\": \"Sucrose gradient sedimentation, RNase A/high-salt-resistant co-sedimentation with 18S rRNA and S27a, and indirect immunofluorescence in HeLa cells\",\n      \"pmids\": [\"9705521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of 40S association not established\", \"Nucleolar localization role uncharacterized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining the architecture of the SKI complex established Ski3 as the scaffold and showed helicase catalysis is separable from complex assembly.\",\n      \"evidence\": \"Directed yeast two-hybrid, reciprocal co-immunoprecipitation, and in vivo assays with helicase-dead Ski2p mutants\",\n      \"pmids\": [\"16043509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and quantitative affinities not determined\", \"Structural basis of the interactions not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The crystal structure of the Ski2 helicase region defined its Mtr4-like fold and identified the insertion domain as a broad-specificity RNA-binding module.\",\n      \"evidence\": \"X-ray crystallography at 2.4 \\u00c5 with in vitro RNA-binding and deletion-construct assays\",\n      \"pmids\": [\"22114319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length protein and assembled complex not captured\", \"Mechanism of substrate channeling not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The cryo-EM ribosome-SKI structure resolved the central mechanistic question of how the complex extracts mRNA for decay, showing direct ribosome docking, autoinhibition relief, and 3'-overhang threading into the helicase channel.\",\n      \"evidence\": \"Cryo-EM of an endogenous 80S ribosome-Ski2-Ski3-Ski8 complex at ~4 \\u00c5 core resolution\",\n      \"pmids\": [\"27980209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct handoff to the exosome not captured structurally\", \"Dynamics of mRNA translocation through the channel not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking human SKIC2/exosome activity to viral HBx mRNA decay and to IL-1\\u03b2/ATF3 transcriptional induction connected the decay machinery to inducible antiviral gene regulation.\",\n      \"evidence\": \"Promoter-reporter assays, ChIP for ATF3 binding, siRNA knockdown, and mRNA stability assays\",\n      \"pmids\": [\"30055801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; direct helicase action on HBx mRNA not structurally resolved\", \"Breadth of viral/cellular targets regulated this way unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the human SKI complex physically hands threaded mRNA to the exosome, and the functional role of SKIC2 nucleolar localization, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the human SKI-exosome-ribosome supercomplex\", \"Nucleolar function of human SKIC2 uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"SKI complex (Ski2-Ski3-Ski8)\"],\n    \"partners\": [\"SKIC3\", \"SKIC8\", \"SKI7\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}