{"gene":"SMG8","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2009,"finding":"SMG-8 and SMG-9 were identified as novel subunits of the SMG-1 complex. SMG-8 suppresses SMG-1 kinase activity in the isolated SMG-1 complex and recruits SMG-1 to the mRNA surveillance complex. Inactivation of SMG-8 induces accumulation of a ribosome:Upf1:eRF1:eRF3:EJC complex on mRNP, revealing that SMG-8 is required for proper remodeling of the SURF complex to the DECID complex during NMD.","method":"Co-immunoprecipitation, RNA interference knockdown, ribosome fractionation, mRNP complex analysis in mammals and C. elegans","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockdown with defined molecular phenotype, replicated in two organisms (mammals and nematodes)","pmids":["19417104"],"is_preprint":false},{"year":2011,"finding":"Cryo-EM structural analysis revealed that SMG-8 binds to the N-terminal HEAT repeat region of SMG-1 (scaffolded by SMG-9), and that SMG-8 binding induces large-scale conformational changes in the HEAT repeats that are transmitted to the kinase domain, down-regulating SMG-1 kinase activity on Upf1 without directly contacting the catalytic domain. SMG-9 controls SMG-1 activity indirectly by recruiting SMG-8 to the HEAT repeat region.","method":"Electron microscopy 3D reconstruction, in vitro kinase assays, deletion/mutant analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with in vitro kinase assays, replicated mechanistic findings from PMID:19417104","pmids":["21245168"],"is_preprint":false},{"year":2015,"finding":"Cryo-EM of the SMG-1-8-9-UPF1 complex showed that SMG-8 and SMG-9 interact with the SMG-1 C-terminal insertion domain and promote high-affinity UPF1 binding to SMG-1-8-9, while simultaneously decelerating SMG-1 kinase activity and enhancing stringency of phosphorylation site selection. UPF2 destabilizes the SMG-1-8-9-UPF1 complex, leading to substrate release.","method":"Electron cryo-microscopy, in vitro kinase assays, complex reconstitution","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with multiple functional states, in vitro biochemical validation, orthogonal methods in a single study","pmids":["26130714"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the SMG8-SMG9 core complex from C. elegans at 2.5 Å revealed that SMG8-SMG9 forms a G-domain heterodimer with architectural similarities to dynamin-like GTPases (e.g., Atlastin, GBP1). The heterodimer forms in the absence of nucleotides; nucleotide binding occurs at the G domain of SMG9 but not SMG8. Interactions forming the heterodimer are conserved from worms to humans.","method":"X-ray crystallography (2.5 Å), fitting into EM density maps of human SMG1-SMG8-SMG9","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with conservation analysis across species, single lab","pmids":["28389433"],"is_preprint":false},{"year":2019,"finding":"3.45-Å cryo-EM structure of human SMG1-SMG8-SMG9 revealed the presence of inositol hexaphosphate (InsP6) bound in the SMG1 kinase domain. The InsP6-binding site is required for optimal in vitro phosphorylation of SMG1 substrates. This InsP6-binding site is conserved in mTOR and potentially other PIKK family members.","method":"Cryo-EM at 3.45 Å, mass spectrometry for InsP6 identification, in vitro kinase assay with InsP6-binding site mutants","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structure combined with MS identification and functional mutagenesis in a single study","pmids":["31792449"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structure of the SMG1-SMG8-SMG9 complex at 3.4 Å showed that SMG8 possesses a C-terminal kinase inhibitory domain (KID) that covers the catalytic pocket of SMG1, thereby inhibiting its kinase activity. Structural analyses suggested that GTP hydrolysis by SMG9 would induce a conformational change in SMG8-SMG9 causing the KID to move away from the inhibitory position, restoring SMG1 kinase activity.","method":"Cryo-EM at 3.4 Å, biochemical kinase inhibition assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — near-atomic cryo-EM with biochemical validation, single lab but multiple orthogonal methods","pmids":["31729466"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM reconstructions of SMG1-9 and SMG1-8-9 complexes bound to an inhibitor or non-hydrolyzable ATP analog (2.8–3.6 Å) showed that the SMG1 insertion domain exerts an autoinhibitory function by directly blocking the substrate-binding path and access to the active site, and that this autoinhibitory state is stabilized by the presence of SMG8.","method":"Cryo-EM (2.8–3.6 Å resolution), biochemical analysis with kinase inhibitor and ATP analog","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structures in multiple states with biochemical validation, consistent with prior structural studies","pmids":["34698635"],"is_preprint":false},{"year":2013,"finding":"Knockdown of SMG-8 in patient-derived fibroblasts (Ullrich congenital muscular dystrophy and CARASIL) restored defective mRNA and protein levels from PTC-containing transcripts without affecting cell growth, cell-cycle progression, or ER stress, demonstrating that SMG-8 is a viable target for NMD inhibition with minimal cytotoxicity compared to other NMD factors.","method":"siRNA knockdown screening of 15 NMD factors, RT-PCR and Western blot for NMD substrate rescue, cell growth and cell-cycle assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in patient-derived cells with multiple readouts (mRNA, protein, cell cycle), single lab","pmids":["23983263"],"is_preprint":false},{"year":2020,"finding":"Loss-of-function variants in SMG8 in human patients resulted in a general increase in NMD substrate mRNA levels (RNA-seq) and increased phosphorylation of UPF1 (a key SMG1-dependent step), consistent with loss of SMG8-mediated inhibition of SMG1 kinase activity in vivo.","method":"RNA-seq of patient cells, phospho-UPF1 immunoblotting","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived loss-of-function with two orthogonal readouts (transcriptome-wide NMD substrate levels and UPF1 phosphorylation), single study","pmids":["33242396"],"is_preprint":false},{"year":2022,"finding":"CRISPR-Cas9 genome-wide screen identified that loss of SMG8 (or SMG9) causes resistance to ATR inhibitors via an SMG1-mediated mechanism. SMG8/9-defective cells showed reduced ATRi-induced transcription/replication conflicts (TRCs) and lacked characteristic ATRi responses (changes in ATM/CHK2, γH2AX, phospho-RPA, 53BP1), indicating that the SMG8/9/SMG1 pathway modulates cellular responses to replication stress.","method":"Genome-wide CRISPR-Cas9 positive selection screen, ATR inhibitor treatment, immunofluorescence and immunoblotting for DNA damage markers, TRC measurement","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen with mechanistic follow-up using multiple markers, single lab","pmids":["36273494"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, smg-8 mutations do not affect degradation of endogenous NMD targets (rpl-7a, rpl-12, unc-54(r293)) or exogenous NMD reporters, and smg-8 animals lack classical Smg mutant phenotypes, indicating that C. elegans SMG-8 is not a critical NMD component (negative finding, potentially species-specific).","method":"Genetic analysis using four independent NMD assays (endogenous NMD targets, exogenous reporter), phenotypic analysis of smg-8 mutants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — four independent genetic assays in C. elegans, single lab; this is a negative result contrasting mammalian data","pmids":["23166684"],"is_preprint":false},{"year":2026,"finding":"Deletion of the SMG8 kinase inhibitory domain (KID) in human cells did not affect UPF1 phosphorylation or NMD efficiency in vivo, demonstrating the KID is dispensable for NMD in intact cells. Complete loss of SMG8 caused only modest NMD impairment with moderately increased UPF1 phosphorylation. However, SMG8-deficient cells showed pronounced hypersensitivity to partial pharmacological SMG1 inhibition, establishing SMG8 as a nonessential modulator that safeguards NMD efficiency and perturbation tolerance.","method":"CRISPR-Cas9 deletion of SMG8 KID and full SMG8 in multiple human cell lines, RNA-seq for NMD substrate levels, phospho-UPF1 immunoblotting, pharmacological SMG1 inhibitor treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic and pharmacological perturbations across multiple human cell lines with transcriptome-wide and biochemical readouts, replicated across cellular contexts","pmids":["41830328"],"is_preprint":false}],"current_model":"SMG8 is a regulatory subunit of the SMG1 kinase complex (SMG1C) that binds SMG1 via its N-terminal HEAT repeat region (scaffolded by SMG9, which recruits SMG8) and inhibits SMG1 kinase activity through a C-terminal kinase inhibitory domain (KID) that occludes the catalytic pocket, stabilizing an autoinhibitory conformation; SMG8 also promotes UPF1 substrate recruitment and phosphorylation site stringency, recruits SMG1 to the mRNA surveillance complex, and in human cells acts as a nonessential modulator that safeguards NMD efficiency and perturbation tolerance rather than being absolutely required for basal NMD."},"narrative":{"mechanistic_narrative":"SMG8 is a regulatory subunit of the SMG1 kinase complex (SMG1C) that tunes nonsense-mediated mRNA decay (NMD) by controlling the timing and stringency of SMG1-dependent UPF1 phosphorylation [PMID:19417104, PMID:26130714]. Together with SMG9 it forms a G-domain heterodimer architecturally related to dynamin-like GTPases, in which nucleotide binds the SMG9 G domain rather than SMG8 [PMID:28389433]; SMG9 scaffolds this module onto the N-terminal HEAT-repeat region of SMG1 and thereby recruits SMG8 [PMID:21245168]. SMG8 binding drives large-scale HEAT-repeat conformational changes that propagate to and downregulate the SMG1 kinase domain, and its C-terminal kinase inhibitory domain (KID) caps the catalytic pocket to stabilize an autoinhibitory state of the SMG1 insertion domain [PMID:21245168, PMID:31729466, PMID:34698635]. Within the SMG1-8-9-UPF1 assembly, SMG8/SMG9 promote high-affinity UPF1 capture while decelerating the kinase and enhancing phosphosite stringency, with UPF2 destabilizing the complex to release substrate [PMID:26130714]. SMG8 also recruits SMG1 to the mRNA surveillance complex and is required for remodeling of the SURF complex into the DECID complex during NMD [PMID:19417104]. In human cells SMG8 is a nonessential modulator: full loss causes only modest NMD impairment and the KID is dispensable for NMD in intact cells, yet SMG8-deficient cells become hypersensitive to partial SMG1 inhibition, defining a role in safeguarding NMD efficiency and perturbation tolerance [PMID:41830328]. Loss-of-function in patients elevates NMD-substrate transcripts and UPF1 phosphorylation, consistent with relief of SMG1 inhibition in vivo [PMID:33242396], and loss of SMG8/SMG9 confers resistance to ATR inhibitors through an SMG1-mediated effect on replication stress responses [PMID:36273494].","teleology":[{"year":2009,"claim":"Established SMG8 as a bona fide subunit of the SMG1 complex with dual regulatory roles, answering whether NMD kinase activity is gated by dedicated accessory factors.","evidence":"Co-IP, RNAi knockdown, and mRNP/ribosome fractionation in mammals and C. elegans","pmids":["19417104"],"confidence":"High","gaps":["Structural basis of kinase suppression unresolved","Molecular mechanism of SURF-to-DECID remodeling not defined"]},{"year":2011,"claim":"Resolved how SMG8 represses SMG1 without contacting the active site, showing allosteric control via the HEAT repeats and SMG9-dependent recruitment.","evidence":"EM 3D reconstruction with in vitro kinase and deletion/mutant assays","pmids":["21245168"],"confidence":"High","gaps":["Atomic-resolution view of the inhibited kinase lacking","How conformational signal reaches catalytic pocket not pinpointed"]},{"year":2015,"claim":"Showed SMG8/SMG9 couple substrate recruitment to kinase regulation, capturing UPF1 with high affinity while slowing phosphorylation and sharpening site selection.","evidence":"Cryo-EM of SMG1-8-9-UPF1 in multiple states with in vitro kinase assays and reconstitution","pmids":["26130714"],"confidence":"High","gaps":["Trigger that converts the complex from inhibited to active not defined","UPF2-mediated release kinetics in vivo unknown"]},{"year":2017,"claim":"Defined the SMG8-SMG9 core as a nucleotide-asymmetric G-domain heterodimer resembling dynamin-like GTPases, framing how a GTPase module could gate the kinase.","evidence":"2.5 Å X-ray crystallography of C. elegans core with EM map fitting and conservation analysis","pmids":["28389433"],"confidence":"High","gaps":["Functional consequence of SMG9 nucleotide binding in NMD not tested","Whether GTP turnover drives kinase activation unresolved"]},{"year":2019,"claim":"Defined the molecular basis of SMG1 autoinhibition within the SMG1-8-9 complex: an SMG8 KID occludes the catalytic pocket and an InsP6 cofactor is required for optimal substrate phosphorylation.","evidence":"Cryo-EM at 3.4–3.45 Å, MS identification of InsP6, and in vitro kinase assays with binding-site mutants","pmids":["31729466","31792449"],"confidence":"High","gaps":["Direct demonstration that SMG9 GTP hydrolysis displaces the KID lacking","InsP6 dependence in cellular NMD not established"]},{"year":2021,"claim":"Clarified that SMG8 acts by stabilizing an intrinsic SMG1 autoinhibitory state in which the insertion domain blocks substrate access, refining the inhibition model.","evidence":"Cryo-EM (2.8–3.6 Å) of SMG1-9 and SMG1-8-9 with inhibitor and non-hydrolyzable ATP analog plus biochemical analysis","pmids":["34698635"],"confidence":"High","gaps":["Physiological cue that relieves autoinhibition not identified","Dynamics of insertion-domain release not captured"]},{"year":2012,"claim":"Revealed species divergence by showing C. elegans smg-8 is dispensable for NMD, signaling that SMG8's contribution is not uniform across organisms.","evidence":"Four independent genetic NMD assays and phenotypic analysis of smg-8 mutants in C. elegans","pmids":["23166684"],"confidence":"Medium","gaps":["Negative result; does not exclude conditional requirement","Contrasts mammalian data without reconciling mechanism"]},{"year":2013,"claim":"Demonstrated therapeutic relevance by showing SMG8 knockdown restores PTC-bearing transcripts and proteins with minimal cytotoxicity, nominating it as a low-toxicity NMD-inhibition target.","evidence":"siRNA screen of NMD factors in patient fibroblasts with mRNA/protein rescue and cell growth/cycle assays","pmids":["23983263"],"confidence":"Medium","gaps":["Magnitude of NMD inhibition versus other factors not quantified mechanistically","Single lab, limited disease contexts"]},{"year":2020,"claim":"Confirmed in human patients that SMG8 loss relieves SMG1 inhibition in vivo, linking genetic deficiency to elevated UPF1 phosphorylation and NMD-substrate accumulation.","evidence":"RNA-seq and phospho-UPF1 immunoblotting in patient cells with loss-of-function variants","pmids":["33242396"],"confidence":"Medium","gaps":["Disease mechanism downstream of dysregulated NMD not defined","Single study"]},{"year":2022,"claim":"Connected the SMG8/SMG9/SMG1 axis to replication stress, showing its loss confers ATR-inhibitor resistance by dampening transcription/replication conflicts.","evidence":"Genome-wide CRISPR-Cas9 resistance screen with DNA-damage marker imaging/immunoblotting and TRC measurement","pmids":["36273494"],"confidence":"Medium","gaps":["Direct molecular link between NMD kinase control and TRCs unresolved","SMG1 substrates mediating the response not identified"]},{"year":2026,"claim":"Reframed SMG8 as a nonessential safeguard rather than a core NMD factor, showing the KID is dispensable in cells and full loss is only modestly impairing yet sensitizes cells to SMG1 inhibition.","evidence":"CRISPR deletion of SMG8 KID and full SMG8 across multiple human cell lines with RNA-seq, phospho-UPF1 immunoblotting, and pharmacological SMG1 inhibition","pmids":["41830328"],"confidence":"High","gaps":["Reconciliation of in-cell KID dispensability with in vitro structural inhibition not fully explained","Conditions under which SMG8 becomes critical not enumerated"]},{"year":null,"claim":"The physiological trigger that converts the SMG8-stabilized autoinhibited SMG1 complex into an active kinase, and whether SMG9 GTP hydrolysis drives KID displacement in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No in vivo demonstration of GTP-hydrolysis-coupled activation","Cellular signal/cofactor that times kinase activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,5,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,8,11]}],"complexes":["SMG1 kinase complex (SMG1C / SMG1-SMG8-SMG9)"],"partners":["SMG1","SMG9","UPF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8ND04","full_name":"Nonsense-mediated mRNA decay factor SMG8","aliases":["Amplified in breast cancer gene 2 protein","Protein smg-8 homolog"],"length_aa":991,"mass_kda":109.7,"function":"Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Is recruited by release factors to stalled ribosomes together with SMG1 and SMG9 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required to mediate the recruitment of SMG1 to the ribosome:SURF complex and to suppress SMG1 kinase activity until the ribosome:SURF complex locates the exon junction complex (EJC). Acts as a regulator of kinase activity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8ND04/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMG8","classification":"Not Classified","n_dependent_lines":325,"n_total_lines":1208,"dependency_fraction":0.26903973509933776},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CETN3","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SMG8","total_profiled":1310},"omim":[{"mim_id":"619268","title":"ALZAHRANI-KUWAHARA SYNDROME; ALKUS","url":"https://www.omim.org/entry/619268"},{"mim_id":"613176","title":"SMG9 NONSENSE-MEDIATED mRNA DECAY FACTOR; SMG9","url":"https://www.omim.org/entry/613176"},{"mim_id":"613175","title":"SMG8 NONSENSE-MEDIATED mRNA DECAY FACTOR; SMG8","url":"https://www.omim.org/entry/613175"},{"mim_id":"607032","title":"SMG1 NONSENSE-MEDIATED mRNA DECAY-ASSOCIATED PI3K-RELATED KINASE; SMG1","url":"https://www.omim.org/entry/607032"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMG8"},"hgnc":{"alias_symbol":["FLJ10587","FLJ23205"],"prev_symbol":["C17orf71"]},"alphafold":{"accession":"Q8ND04","domains":[{"cath_id":"-","chopping":"6-18_43-80_134-277_295-342_416-488","consensus_level":"high","plddt":85.6185,"start":6,"end":488},{"cath_id":"-","chopping":"508-561","consensus_level":"high","plddt":94.5498,"start":508,"end":561},{"cath_id":"-","chopping":"567-605","consensus_level":"medium","plddt":87.1226,"start":567,"end":605},{"cath_id":"-","chopping":"607-665_741-803_840-991","consensus_level":"medium","plddt":88.9403,"start":607,"end":991}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND04","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND04-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND04-F1-predicted_aligned_error_v6.png","plddt_mean":73.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMG8","jax_strain_url":"https://www.jax.org/strain/search?query=SMG8"},"sequence":{"accession":"Q8ND04","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8ND04.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8ND04/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND04"}},"corpus_meta":[{"pmid":"19417104","id":"PMC_19417104","title":"SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19417104","citation_count":199,"is_preprint":false},{"pmid":"21245168","id":"PMC_21245168","title":"The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21245168","citation_count":71,"is_preprint":false},{"pmid":"26130714","id":"PMC_26130714","title":"A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26130714","citation_count":52,"is_preprint":false},{"pmid":"31792449","id":"PMC_31792449","title":"InsP6 binding to PIKK kinases revealed by the cryo-EM structure of an SMG1-SMG8-SMG9 complex.","date":"2019","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31792449","citation_count":31,"is_preprint":false},{"pmid":"23983263","id":"PMC_23983263","title":"Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23983263","citation_count":28,"is_preprint":false},{"pmid":"31729466","id":"PMC_31729466","title":"Cryo-EM structure of SMG1-SMG8-SMG9 complex.","date":"2019","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31729466","citation_count":27,"is_preprint":false},{"pmid":"34698635","id":"PMC_34698635","title":"Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34698635","citation_count":26,"is_preprint":false},{"pmid":"33242396","id":"PMC_33242396","title":"Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33242396","citation_count":25,"is_preprint":false},{"pmid":"36273494","id":"PMC_36273494","title":"SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.","date":"2022","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36273494","citation_count":14,"is_preprint":false},{"pmid":"28389433","id":"PMC_28389433","title":"Structure of a SMG8-SMG9 complex identifies a G-domain heterodimer in the NMD effector proteins.","date":"2017","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28389433","citation_count":11,"is_preprint":false},{"pmid":"23166684","id":"PMC_23166684","title":"Genetic characterization of smg-8 mutants reveals no role in C. elegans nonsense mediated decay.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23166684","citation_count":11,"is_preprint":false},{"pmid":"34761517","id":"PMC_34761517","title":"Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9-associated disease trait.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34761517","citation_count":5,"is_preprint":false},{"pmid":"37194129","id":"PMC_37194129","title":"Expanding the genetic spectrum of ALKU syndrome: Compound heterozygosity for two deleterious variants in SMG8 gene.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37194129","citation_count":1,"is_preprint":false},{"pmid":"41830328","id":"PMC_41830328","title":"SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay.","date":"2026","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/41830328","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8701,"output_tokens":3326,"usd":0.037997,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10827,"output_tokens":3618,"usd":0.072292,"stage2_stop_reason":"end_turn"},"total_usd":0.110289,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"SMG-8 and SMG-9 were identified as novel subunits of the SMG-1 complex. SMG-8 suppresses SMG-1 kinase activity in the isolated SMG-1 complex and recruits SMG-1 to the mRNA surveillance complex. Inactivation of SMG-8 induces accumulation of a ribosome:Upf1:eRF1:eRF3:EJC complex on mRNP, revealing that SMG-8 is required for proper remodeling of the SURF complex to the DECID complex during NMD.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown, ribosome fractionation, mRNP complex analysis in mammals and C. elegans\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockdown with defined molecular phenotype, replicated in two organisms (mammals and nematodes)\",\n      \"pmids\": [\"19417104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cryo-EM structural analysis revealed that SMG-8 binds to the N-terminal HEAT repeat region of SMG-1 (scaffolded by SMG-9), and that SMG-8 binding induces large-scale conformational changes in the HEAT repeats that are transmitted to the kinase domain, down-regulating SMG-1 kinase activity on Upf1 without directly contacting the catalytic domain. SMG-9 controls SMG-1 activity indirectly by recruiting SMG-8 to the HEAT repeat region.\",\n      \"method\": \"Electron microscopy 3D reconstruction, in vitro kinase assays, deletion/mutant analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with in vitro kinase assays, replicated mechanistic findings from PMID:19417104\",\n      \"pmids\": [\"21245168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cryo-EM of the SMG-1-8-9-UPF1 complex showed that SMG-8 and SMG-9 interact with the SMG-1 C-terminal insertion domain and promote high-affinity UPF1 binding to SMG-1-8-9, while simultaneously decelerating SMG-1 kinase activity and enhancing stringency of phosphorylation site selection. UPF2 destabilizes the SMG-1-8-9-UPF1 complex, leading to substrate release.\",\n      \"method\": \"Electron cryo-microscopy, in vitro kinase assays, complex reconstitution\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with multiple functional states, in vitro biochemical validation, orthogonal methods in a single study\",\n      \"pmids\": [\"26130714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the SMG8-SMG9 core complex from C. elegans at 2.5 Å revealed that SMG8-SMG9 forms a G-domain heterodimer with architectural similarities to dynamin-like GTPases (e.g., Atlastin, GBP1). The heterodimer forms in the absence of nucleotides; nucleotide binding occurs at the G domain of SMG9 but not SMG8. Interactions forming the heterodimer are conserved from worms to humans.\",\n      \"method\": \"X-ray crystallography (2.5 Å), fitting into EM density maps of human SMG1-SMG8-SMG9\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with conservation analysis across species, single lab\",\n      \"pmids\": [\"28389433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"3.45-Å cryo-EM structure of human SMG1-SMG8-SMG9 revealed the presence of inositol hexaphosphate (InsP6) bound in the SMG1 kinase domain. The InsP6-binding site is required for optimal in vitro phosphorylation of SMG1 substrates. This InsP6-binding site is conserved in mTOR and potentially other PIKK family members.\",\n      \"method\": \"Cryo-EM at 3.45 Å, mass spectrometry for InsP6 identification, in vitro kinase assay with InsP6-binding site mutants\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structure combined with MS identification and functional mutagenesis in a single study\",\n      \"pmids\": [\"31792449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure of the SMG1-SMG8-SMG9 complex at 3.4 Å showed that SMG8 possesses a C-terminal kinase inhibitory domain (KID) that covers the catalytic pocket of SMG1, thereby inhibiting its kinase activity. Structural analyses suggested that GTP hydrolysis by SMG9 would induce a conformational change in SMG8-SMG9 causing the KID to move away from the inhibitory position, restoring SMG1 kinase activity.\",\n      \"method\": \"Cryo-EM at 3.4 Å, biochemical kinase inhibition assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — near-atomic cryo-EM with biochemical validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31729466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM reconstructions of SMG1-9 and SMG1-8-9 complexes bound to an inhibitor or non-hydrolyzable ATP analog (2.8–3.6 Å) showed that the SMG1 insertion domain exerts an autoinhibitory function by directly blocking the substrate-binding path and access to the active site, and that this autoinhibitory state is stabilized by the presence of SMG8.\",\n      \"method\": \"Cryo-EM (2.8–3.6 Å resolution), biochemical analysis with kinase inhibitor and ATP analog\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structures in multiple states with biochemical validation, consistent with prior structural studies\",\n      \"pmids\": [\"34698635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of SMG-8 in patient-derived fibroblasts (Ullrich congenital muscular dystrophy and CARASIL) restored defective mRNA and protein levels from PTC-containing transcripts without affecting cell growth, cell-cycle progression, or ER stress, demonstrating that SMG-8 is a viable target for NMD inhibition with minimal cytotoxicity compared to other NMD factors.\",\n      \"method\": \"siRNA knockdown screening of 15 NMD factors, RT-PCR and Western blot for NMD substrate rescue, cell growth and cell-cycle assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in patient-derived cells with multiple readouts (mRNA, protein, cell cycle), single lab\",\n      \"pmids\": [\"23983263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss-of-function variants in SMG8 in human patients resulted in a general increase in NMD substrate mRNA levels (RNA-seq) and increased phosphorylation of UPF1 (a key SMG1-dependent step), consistent with loss of SMG8-mediated inhibition of SMG1 kinase activity in vivo.\",\n      \"method\": \"RNA-seq of patient cells, phospho-UPF1 immunoblotting\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived loss-of-function with two orthogonal readouts (transcriptome-wide NMD substrate levels and UPF1 phosphorylation), single study\",\n      \"pmids\": [\"33242396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR-Cas9 genome-wide screen identified that loss of SMG8 (or SMG9) causes resistance to ATR inhibitors via an SMG1-mediated mechanism. SMG8/9-defective cells showed reduced ATRi-induced transcription/replication conflicts (TRCs) and lacked characteristic ATRi responses (changes in ATM/CHK2, γH2AX, phospho-RPA, 53BP1), indicating that the SMG8/9/SMG1 pathway modulates cellular responses to replication stress.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 positive selection screen, ATR inhibitor treatment, immunofluorescence and immunoblotting for DNA damage markers, TRC measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen with mechanistic follow-up using multiple markers, single lab\",\n      \"pmids\": [\"36273494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, smg-8 mutations do not affect degradation of endogenous NMD targets (rpl-7a, rpl-12, unc-54(r293)) or exogenous NMD reporters, and smg-8 animals lack classical Smg mutant phenotypes, indicating that C. elegans SMG-8 is not a critical NMD component (negative finding, potentially species-specific).\",\n      \"method\": \"Genetic analysis using four independent NMD assays (endogenous NMD targets, exogenous reporter), phenotypic analysis of smg-8 mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four independent genetic assays in C. elegans, single lab; this is a negative result contrasting mammalian data\",\n      \"pmids\": [\"23166684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Deletion of the SMG8 kinase inhibitory domain (KID) in human cells did not affect UPF1 phosphorylation or NMD efficiency in vivo, demonstrating the KID is dispensable for NMD in intact cells. Complete loss of SMG8 caused only modest NMD impairment with moderately increased UPF1 phosphorylation. However, SMG8-deficient cells showed pronounced hypersensitivity to partial pharmacological SMG1 inhibition, establishing SMG8 as a nonessential modulator that safeguards NMD efficiency and perturbation tolerance.\",\n      \"method\": \"CRISPR-Cas9 deletion of SMG8 KID and full SMG8 in multiple human cell lines, RNA-seq for NMD substrate levels, phospho-UPF1 immunoblotting, pharmacological SMG1 inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic and pharmacological perturbations across multiple human cell lines with transcriptome-wide and biochemical readouts, replicated across cellular contexts\",\n      \"pmids\": [\"41830328\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMG8 is a regulatory subunit of the SMG1 kinase complex (SMG1C) that binds SMG1 via its N-terminal HEAT repeat region (scaffolded by SMG9, which recruits SMG8) and inhibits SMG1 kinase activity through a C-terminal kinase inhibitory domain (KID) that occludes the catalytic pocket, stabilizing an autoinhibitory conformation; SMG8 also promotes UPF1 substrate recruitment and phosphorylation site stringency, recruits SMG1 to the mRNA surveillance complex, and in human cells acts as a nonessential modulator that safeguards NMD efficiency and perturbation tolerance rather than being absolutely required for basal NMD.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMG8 is a regulatory subunit of the SMG1 kinase complex (SMG1C) that tunes nonsense-mediated mRNA decay (NMD) by controlling the timing and stringency of SMG1-dependent UPF1 phosphorylation [#0, #2]. Together with SMG9 it forms a G-domain heterodimer architecturally related to dynamin-like GTPases, in which nucleotide binds the SMG9 G domain rather than SMG8 [#3]; SMG9 scaffolds this module onto the N-terminal HEAT-repeat region of SMG1 and thereby recruits SMG8 [#1]. SMG8 binding drives large-scale HEAT-repeat conformational changes that propagate to and downregulate the SMG1 kinase domain, and its C-terminal kinase inhibitory domain (KID) caps the catalytic pocket to stabilize an autoinhibitory state of the SMG1 insertion domain [#1, #5, #6]. Within the SMG1-8-9-UPF1 assembly, SMG8/SMG9 promote high-affinity UPF1 capture while decelerating the kinase and enhancing phosphosite stringency, with UPF2 destabilizing the complex to release substrate [#2]. SMG8 also recruits SMG1 to the mRNA surveillance complex and is required for remodeling of the SURF complex into the DECID complex during NMD [#0]. In human cells SMG8 is a nonessential modulator: full loss causes only modest NMD impairment and the KID is dispensable for NMD in intact cells, yet SMG8-deficient cells become hypersensitive to partial SMG1 inhibition, defining a role in safeguarding NMD efficiency and perturbation tolerance [#11]. Loss-of-function in patients elevates NMD-substrate transcripts and UPF1 phosphorylation, consistent with relief of SMG1 inhibition in vivo [#8], and loss of SMG8/SMG9 confers resistance to ATR inhibitors through an SMG1-mediated effect on replication stress responses [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established SMG8 as a bona fide subunit of the SMG1 complex with dual regulatory roles, answering whether NMD kinase activity is gated by dedicated accessory factors.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, and mRNP/ribosome fractionation in mammals and C. elegans\",\n      \"pmids\": [\"19417104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of kinase suppression unresolved\", \"Molecular mechanism of SURF-to-DECID remodeling not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how SMG8 represses SMG1 without contacting the active site, showing allosteric control via the HEAT repeats and SMG9-dependent recruitment.\",\n      \"evidence\": \"EM 3D reconstruction with in vitro kinase and deletion/mutant assays\",\n      \"pmids\": [\"21245168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution view of the inhibited kinase lacking\", \"How conformational signal reaches catalytic pocket not pinpointed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SMG8/SMG9 couple substrate recruitment to kinase regulation, capturing UPF1 with high affinity while slowing phosphorylation and sharpening site selection.\",\n      \"evidence\": \"Cryo-EM of SMG1-8-9-UPF1 in multiple states with in vitro kinase assays and reconstitution\",\n      \"pmids\": [\"26130714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that converts the complex from inhibited to active not defined\", \"UPF2-mediated release kinetics in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the SMG8-SMG9 core as a nucleotide-asymmetric G-domain heterodimer resembling dynamin-like GTPases, framing how a GTPase module could gate the kinase.\",\n      \"evidence\": \"2.5 Å X-ray crystallography of C. elegans core with EM map fitting and conservation analysis\",\n      \"pmids\": [\"28389433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of SMG9 nucleotide binding in NMD not tested\", \"Whether GTP turnover drives kinase activation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the molecular basis of SMG1 autoinhibition within the SMG1-8-9 complex: an SMG8 KID occludes the catalytic pocket and an InsP6 cofactor is required for optimal substrate phosphorylation.\",\n      \"evidence\": \"Cryo-EM at 3.4–3.45 Å, MS identification of InsP6, and in vitro kinase assays with binding-site mutants\",\n      \"pmids\": [\"31729466\", \"31792449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that SMG9 GTP hydrolysis displaces the KID lacking\", \"InsP6 dependence in cellular NMD not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Clarified that SMG8 acts by stabilizing an intrinsic SMG1 autoinhibitory state in which the insertion domain blocks substrate access, refining the inhibition model.\",\n      \"evidence\": \"Cryo-EM (2.8–3.6 Å) of SMG1-9 and SMG1-8-9 with inhibitor and non-hydrolyzable ATP analog plus biochemical analysis\",\n      \"pmids\": [\"34698635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological cue that relieves autoinhibition not identified\", \"Dynamics of insertion-domain release not captured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed species divergence by showing C. elegans smg-8 is dispensable for NMD, signaling that SMG8's contribution is not uniform across organisms.\",\n      \"evidence\": \"Four independent genetic NMD assays and phenotypic analysis of smg-8 mutants in C. elegans\",\n      \"pmids\": [\"23166684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; does not exclude conditional requirement\", \"Contrasts mammalian data without reconciling mechanism\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated therapeutic relevance by showing SMG8 knockdown restores PTC-bearing transcripts and proteins with minimal cytotoxicity, nominating it as a low-toxicity NMD-inhibition target.\",\n      \"evidence\": \"siRNA screen of NMD factors in patient fibroblasts with mRNA/protein rescue and cell growth/cycle assays\",\n      \"pmids\": [\"23983263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Magnitude of NMD inhibition versus other factors not quantified mechanistically\", \"Single lab, limited disease contexts\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed in human patients that SMG8 loss relieves SMG1 inhibition in vivo, linking genetic deficiency to elevated UPF1 phosphorylation and NMD-substrate accumulation.\",\n      \"evidence\": \"RNA-seq and phospho-UPF1 immunoblotting in patient cells with loss-of-function variants\",\n      \"pmids\": [\"33242396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease mechanism downstream of dysregulated NMD not defined\", \"Single study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected the SMG8/SMG9/SMG1 axis to replication stress, showing its loss confers ATR-inhibitor resistance by dampening transcription/replication conflicts.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 resistance screen with DNA-damage marker imaging/immunoblotting and TRC measurement\",\n      \"pmids\": [\"36273494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between NMD kinase control and TRCs unresolved\", \"SMG1 substrates mediating the response not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reframed SMG8 as a nonessential safeguard rather than a core NMD factor, showing the KID is dispensable in cells and full loss is only modestly impairing yet sensitizes cells to SMG1 inhibition.\",\n      \"evidence\": \"CRISPR deletion of SMG8 KID and full SMG8 across multiple human cell lines with RNA-seq, phospho-UPF1 immunoblotting, and pharmacological SMG1 inhibition\",\n      \"pmids\": [\"41830328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of in-cell KID dispensability with in vitro structural inhibition not fully explained\", \"Conditions under which SMG8 becomes critical not enumerated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological trigger that converts the SMG8-stabilized autoinhibited SMG1 complex into an active kinase, and whether SMG9 GTP hydrolysis drives KID displacement in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo demonstration of GTP-hydrolysis-coupled activation\", \"Cellular signal/cofactor that times kinase activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 8, 11]}\n    ],\n    \"complexes\": [\"SMG1 kinase complex (SMG1C / SMG1-SMG8-SMG9)\"],\n    \"partners\": [\"SMG1\", \"SMG9\", \"UPF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}