{"gene":"SMG7","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2005,"finding":"Crystal structure of the N-terminal domain of SMG7 reveals a 14-3-3-like domain. Residues equivalent to phosphoserine-binding residues in canonical 14-3-3 proteins are conserved in SMG7 and mediate binding to phosphorylated UPF1. Mutation of these residues impairs UPF1 binding to SMG7 in vitro and UPF1 recruitment to cytoplasmic mRNA decay foci in vivo, establishing SMG7 as a phospho-adaptor that targets mRNAs associated with phosphorylated UPF1 for degradation.","method":"X-ray crystallography, in vitro binding assay with phosphoserine mutants, in vivo localization (mRNA decay foci)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validated both in vitro and in vivo, single rigorous study with multiple orthogonal methods","pmids":["15721257"],"is_preprint":false},{"year":2003,"finding":"Human SMG7 (hSmg5/7a) copurifies with UPF1, UPF2, UPF3X, SMG1, and the catalytic subunit of protein phosphatase 2A (PP2A), and functions in dephosphorylation of UPF1 but not UPF2, indicating that SMG7 targets PP2A to UPF1. SMG7 is predominantly cytoplasmic in HEK293T cells.","method":"Co-purification/Co-IP, dephosphorylation assay, subcellular fractionation/Western blot","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-purification with functional dephosphorylation assay in single lab, two orthogonal methods","pmids":["12554878"],"is_preprint":false},{"year":1999,"finding":"C. elegans smg-7 is required for nonsense-mediated mRNA decay; null alleles of smg-7 confer temperature-sensitive stabilization of nonsense mutant mRNAs, establishing smg-7 as an essential NMD factor in vivo.","method":"Genetic screen, cloning, null allele analysis, mRNA stability assay","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans ortholog with mRNA stability readout, single lab","pmids":["9927455"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the C. elegans SMG5-SMG7 complex shows the two 14-3-3-like domains heterodimerize in an unusual perpendicular back-to-back orientation. Structure-based mutants confirm the heterodimer interface is conserved and essential for efficient NMD in human cells. Heterodimerization increases the affinity of the SMG5-SMG7 complex for phosphorylated UPF1, and the degradative activity of the SMG5-SMG7 complex resides specifically in SMG7.","method":"X-ray crystallography, structure-based mutagenesis, NMD functional assay in human cells, binding affinity measurements","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with structure-based mutagenesis validated by functional assays in human cells, multiple orthogonal methods","pmids":["23348841"],"is_preprint":false},{"year":2014,"finding":"In vitro reconstitution with purified components shows that a short C-terminal segment of phosphorylated UPF1 containing the last two Ser-Gln motifs is recognized by the SMG5-SMG7 heterodimer of 14-3-3-like proteins. SMG5 and SMG7 form a heterodimer, whereas the SMG6 14-3-3-like domain is monomeric. The dominant SMG6-UPF1 interaction is phosphorylation-independent, establishing that SMG5-SMG7 and SMG6 have distinct, non-overlapping modes of UPF1 recognition.","method":"In vitro reconstitution with purified components, crystal structure of SMG6 14-3-3-like domain, binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components plus crystal structure and binding assays, multiple orthogonal methods","pmids":["25013172"],"is_preprint":false},{"year":2016,"finding":"SMG6 and SMG7 act on essentially the same endogenous NMD target transcripts, indicating extensive redundancy between the endonucleolytic (SMG6) and exonucleolytic (SMG7) decay routes. NMD target features include introns in 3' UTRs, upstream ORFs, and long 3' UTRs.","method":"Transcriptome profiling of knockdowns and rescues of UPF1, SMG6, and SMG7; meta-analysis","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide knockdown/rescue in human cells, single lab with combinatorial approach","pmids":["27864472"],"is_preprint":false},{"year":2016,"finding":"SMG7 is a novel p53-binding protein that promotes DNA damage-induced p53 stabilization. SMG7 knockout abrogates DNA damage-induced p53 stabilization and impairs p53-mediated p21 activation and cell cycle arrest. SMG7 physically interacts with Mdm2 and promotes ATM-mediated inhibitory phosphorylation of Mdm2 following ionizing radiation, thereby preventing Mdm2-mediated p53 degradation.","method":"Somatic gene knockout, Co-IP (SMG7-p53 and SMG7-Mdm2), Mdm2 phosphorylation assay, cell cycle analysis","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — somatic KO with defined phenotype plus Co-IP and phosphorylation assay, single lab","pmids":["27462439"],"is_preprint":false},{"year":2021,"finding":"Loss of the SMG5-SMG7 pathway also inactivates the SMG6 endonucleolytic branch, demonstrating an unexpected functional dependency. Either SMG5 or SMG7 alone is sufficient to support SMG6-mediated endonucleolysis of NMD targets, establishing a two-factor authentication model where UPF1 phosphorylation and SMG5-SMG7 recruitment are both required to access SMG6 activity.","method":"siRNA depletion of SMG5 and SMG7, transcriptome-wide analysis, functional NMD assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide depletion with functional assays, single lab, multiple methods","pmids":["34172724"],"is_preprint":false},{"year":2012,"finding":"SMG7 interacts with SMG5 but not with PNRC2; PNRC2 preferentially complexes with SMG5. Tethering experiments show that SMG6 is required for UPF1-mediated efficient mRNA degradation. SMG5/SMG7-dependent NMD substrates show less overlap with PNRC2-dependent NMD substrates, suggesting partial segregation of NMD pathways.","method":"Co-IP, microarray analysis, tethering assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with microarray and tethering assays, single lab","pmids":["23234702"],"is_preprint":false},{"year":2018,"finding":"SMG7 interacts with SMG5 (confirmed by Co-IP), and this SMG5-SMG7 complex is functionally required for NMD. In contrast, no physical or functional interaction between SMG5 and PNRC2 was detected. UPF1 interacts with PNRC2 and triggers 5'-3' exonucleolytic decay in tethering assays; PNRC2 knockdown does not affect NMD reporter RNA levels, indicating PNRC2 is not required for NMD.","method":"Co-IP, tethering assay, siRNA knockdown, NMD reporter assay","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP combined with functional tethering and knockdown assays, single lab","pmids":["29348139"],"is_preprint":false},{"year":2007,"finding":"Yeast Ebs1p, identified as the putative S. cerevisiae ortholog of human SMG7, physically interacts with the NMD helicase Upf1p. Overexpressed Ebs1p recruits Upf1p into cytoplasmic P-bodies, and Ebs1p itself localizes to P-bodies upon glucose starvation. Both loss and overexpression of Ebs1p stabilize NMD targets.","method":"Sequence alignment, Co-IP, fluorescence microscopy (P-body localization), mRNA stability assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization with functional NMD assay, single lab, yeast ortholog","pmids":["17984081"],"is_preprint":false},{"year":2019,"finding":"SMG7 interacts with the CCR4-NOT deadenylase complex, and loss of the SMG7-deadenylase complex interaction increases the levels of transcripts regulated by UPF1-SMG7. In combination with Ago2 and UPF1, SMG7 mediates miRNA-targeted mRNA degradation in a 3'UTR-length-dependent manner.","method":"Co-IP (Ago2-UPF1-SMG7), siRNA knockdown, RNA-seq, reporter assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP combined with knockdown and transcriptome analysis, single lab","pmids":["31519907"],"is_preprint":false},{"year":2019,"finding":"DNA damage-induced SMG7-p53 binding requires phosphorylated Ser15 on p53. Substitution of conserved lysine K66 in the SMG7 14-3-3-like domain with glutamic acid (K66E) abolishes interactions with p53 and UPF1 in vitro. Unexpectedly, cells expressing SMG7 K66E retain p53 stabilization/activation and fully functional NMD, indicating that phosphoserine-dependent SMG7 binding is not the sole or essential mechanism for these functions.","method":"Knockin mutagenesis (K66E), co-IP, cell cycle and apoptosis assays, NMD reporter assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockin mutagenesis with multiple functional readouts, single lab","pmids":["31511540"],"is_preprint":false},{"year":2021,"finding":"SMG7 is required for ATR-CHK1 axis activation upon genotoxic stress. SMG7-null cells exhibit attenuated phosphorylation of CHK1 and RPA32 and unhindered DNA replication after damage. Through its 14-3-3 domain, SMG7 directly interacts with Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by RAD17-RFC, an essential step for CHK1 activation. SMG7 also controls G2-M transition and facilitates cell cycle recovery from replication stress.","method":"SMG7-null cells, Co-IP (SMG7-RAD17), chromatin fractionation, CHK1/RPA32 phosphorylation assay, DNA fiber assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined signaling phenotype plus Co-IP and chromatin fractionation, single lab, multiple orthogonal methods","pmids":["33820915"],"is_preprint":false},{"year":2024,"finding":"Chemical cross-linking mass spectrometry (CLMS) identifies protein-protein interactions among SMG1, UPF2, and SMG7, revealing UPF2 as a bridging protein between SMG1 and SMG7. The UPF2 N-terminal region mediates most interactions with SMG7, while SMG7 interactions emerge predominantly from connecting loops rather than well-defined secondary structures.","method":"Chemical cross-linking mass spectrometry (CLMS), structural modelling","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cross-linking MS study without orthogonal validation, single lab","pmids":["38542156"],"is_preprint":false}],"current_model":"SMG7 is a 14-3-3-like adaptor protein that, as part of a heterodimer with SMG5, recognizes phosphorylated UPF1 (at C-terminal Ser-Gln motifs phosphorylated by SMG1) to recruit the PP2A phosphatase for UPF1 dephosphorylation and to channel NMD target mRNAs into exonucleolytic decay; SMG7's degradative activity also requires interaction with the CCR4-NOT deadenylase complex, and its presence is required to authorize SMG6-mediated endonucleolytic cleavage, making SMG5-SMG7 an essential upstream licensing factor for both NMD degradation branches. Beyond NMD, SMG7 also functions in the DNA damage response by binding phospho-Ser15-p53, interacting with Mdm2 to promote ATM-mediated inhibitory Mdm2 phosphorylation and p53 stabilization, and by binding phospho-Ser635-RAD17 through its 14-3-3 domain to promote chromatin retention of the 9-1-1 complex and activate ATR-CHK1 signaling."},"narrative":{"mechanistic_narrative":"SMG7 is an essential nonsense-mediated mRNA decay (NMD) factor that operates as a phosphoserine-binding adaptor through an N-terminal 14-3-3-like domain, channeling aberrant transcripts marked by phosphorylated UPF1 into degradation [PMID:15721257, PMID:9927455]. Its 14-3-3-like domain conserves canonical phosphoserine-binding residues that recognize the C-terminal Ser-Gln motifs of UPF1 phosphorylated by SMG1, and mutation of these residues impairs UPF1 binding and recruitment to cytoplasmic mRNA decay foci [PMID:15721257, PMID:25013172]. SMG7 heterodimerizes with SMG5 via a perpendicular back-to-back arrangement of their 14-3-3-like domains; this dimerization raises affinity for phosphorylated UPF1, and the degradative activity of the complex resides specifically in SMG7 [PMID:23348841, PMID:25013172]. SMG7 co-purifies with UPF1/UPF2/UPF3X/SMG1 and the PP2A catalytic subunit, targeting PP2A to dephosphorylate UPF1 [PMID:12554878], while its degradative output requires interaction with the CCR4-NOT deadenylase complex [PMID:31519907]. SMG5-SMG7 and the endonuclease SMG6 act on largely the same NMD targets, and loss of SMG5-SMG7 inactivates the SMG6 branch, establishing SMG5-SMG7 as an upstream licensing factor required to authorize both decay routes [PMID:27864472, PMID:34172724]. Beyond NMD, SMG7 functions in the DNA damage response: it binds phospho-Ser15-p53 and Mdm2 to promote ATM-mediated inhibitory Mdm2 phosphorylation and p53 stabilization [PMID:27462439], and through its 14-3-3 domain binds phospho-Ser635-RAD17 to promote chromatin retention of the 9-1-1 complex and activate ATR-CHK1 signaling [PMID:33820915].","teleology":[{"year":1999,"claim":"Established that smg-7 is a genuine, genetically essential component of NMD in vivo, before any molecular mechanism was known.","evidence":"Genetic screen and null-allele mRNA-stability analysis in C. elegans","pmids":["9927455"],"confidence":"Medium","gaps":["No molecular activity or biochemical partners defined","Ortholog system; human function not addressed"]},{"year":2003,"claim":"Resolved how SMG7 connects to the decay machinery by showing it co-purifies with UPF1/2/3, SMG1 and PP2A and directs UPF1 dephosphorylation, positioning it as a PP2A-targeting adaptor.","evidence":"Co-purification/Co-IP, dephosphorylation assay, subcellular fractionation in human cells","pmids":["12554878"],"confidence":"Medium","gaps":["Direct vs. indirect PP2A recruitment not separated","Structural basis of UPF1 recognition unknown"]},{"year":2005,"claim":"Defined the molecular basis of target recognition by revealing a 14-3-3-like domain whose conserved phosphoserine-binding residues mediate phospho-UPF1 binding and recruitment to decay foci.","evidence":"X-ray crystallography with phosphoserine-mutant binding and in vivo localization","pmids":["15721257"],"confidence":"High","gaps":["Did not address SMG5 partnership","Did not resolve downstream degradation enzymology"]},{"year":2007,"claim":"Linked SMG7 function to P-body-associated decay by showing the yeast ortholog Ebs1p binds Upf1p and recruits it to P-bodies, with both loss and excess stabilizing NMD targets.","evidence":"Co-IP, P-body fluorescence microscopy, mRNA stability in S. cerevisiae","pmids":["17984081"],"confidence":"Medium","gaps":["Ortholog assignment based on sequence; human conservation untested here","Mechanism of biphasic loss/overexpression effect unexplained"]},{"year":2012,"claim":"Distinguished SMG5-SMG7 from PNRC2-dependent routes, showing SMG7 partners SMG5 and that SMG6 is required for efficient UPF1-mediated degradation, indicating segregated decay sub-pathways.","evidence":"Co-IP, microarray, tethering assays in human cells","pmids":["23234702"],"confidence":"Medium","gaps":["Extent of pathway overlap unresolved","Mechanistic basis of substrate segregation unclear"]},{"year":2013,"claim":"Provided the structural logic of the SMG5-SMG7 complex, showing perpendicular heterodimerization of 14-3-3-like domains that boosts phospho-UPF1 affinity and localizing degradative activity to SMG7.","evidence":"Crystal structure of C. elegans SMG5-SMG7 with structure-based mutagenesis validated in human NMD assays","pmids":["23348841"],"confidence":"High","gaps":["Identity of effector engaged by SMG7's degradative region not defined","Human complex structure not solved"]},{"year":2014,"claim":"Reconstituted recognition in vitro, defining that SMG5-SMG7 binds a short phospho-UPF1 segment via two Ser-Gln motifs while monomeric SMG6 uses a phosphorylation-independent mode, establishing distinct non-overlapping UPF1 engagement.","evidence":"In vitro reconstitution with purified components, SMG6 14-3-3 crystal structure, binding assays","pmids":["25013172"],"confidence":"High","gaps":["In-cell coordination of the two recognition modes not addressed","Kinetics of handoff to decay enzymes unknown"]},{"year":2016,"claim":"Mapped the transcriptome-scale division of labor, showing SMG6 and SMG7 act on essentially the same NMD targets, implying redundant endo- and exonucleolytic routes.","evidence":"Transcriptome profiling of UPF1/SMG6/SMG7 knockdown-rescue","pmids":["27864472"],"confidence":"Medium","gaps":["Did not establish hierarchical dependency between branches","Target-feature determinants of branch choice unresolved"]},{"year":2016,"claim":"Extended SMG7 function beyond NMD by identifying it as a p53-binding protein required for DNA-damage-induced p53 stabilization via Mdm2 interaction and ATM-mediated Mdm2 phosphorylation.","evidence":"Somatic knockout, SMG7-p53 and SMG7-Mdm2 Co-IP, Mdm2 phosphorylation and cell-cycle assays","pmids":["27462439"],"confidence":"Medium","gaps":["Direct vs. scaffolded effect on ATM-Mdm2 not separated","Relationship between NMD and DDR roles unclear"]},{"year":2019,"claim":"Connected SMG7 degradative output to a specific effector by showing it binds CCR4-NOT and contributes to Ago2/UPF1-dependent miRNA-targeted mRNA decay in a 3'UTR-length-dependent manner.","evidence":"Co-IP (Ago2-UPF1-SMG7), siRNA knockdown, RNA-seq, reporter assays","pmids":["31519907"],"confidence":"Medium","gaps":["Direct CCR4-NOT contact residues not mapped","Generality across NMD targets vs. miRNA targets unresolved"]},{"year":2019,"claim":"Tested whether phosphoserine binding is the essential mechanism, finding the 14-3-3 K66E mutant abolishes p53/UPF1 binding in vitro yet cells retain p53 activation and functional NMD, revealing phospho-independent contributions.","evidence":"K66E knockin mutagenesis with NMD reporter, cell cycle and apoptosis assays","pmids":["31511540"],"confidence":"Medium","gaps":["Alternative binding surfaces or redundant factors not identified","Reconciliation with strict phospho-dependence seen in vitro unresolved"]},{"year":2019,"claim":"Confirmed the obligate SMG5-SMG7 partnership for NMD while excluding a functional SMG5-PNRC2 axis, clarifying which interactions are necessary for decay.","evidence":"Reciprocal Co-IP, tethering, siRNA knockdown, NMD reporter assays","pmids":["29348139"],"confidence":"Medium","gaps":["PNRC2's role in any subset of substrates not fully excluded"]},{"year":2021,"claim":"Reframed branch redundancy into a licensing hierarchy by showing loss of SMG5-SMG7 inactivates the SMG6 endonucleolytic branch, with either SMG5 or SMG7 sufficient — a two-factor authentication model for accessing SMG6.","evidence":"siRNA depletion of SMG5/SMG7, transcriptome-wide and functional NMD assays","pmids":["34172724"],"confidence":"Medium","gaps":["Molecular signal that authorizes SMG6 not identified","Whether dephosphorylation or recruitment is the licensing trigger unresolved"]},{"year":2021,"claim":"Defined a second DDR role, showing SMG7 is required for ATR-CHK1 activation by binding phospho-Ser635-RAD17 through its 14-3-3 domain and promoting 9-1-1 chromatin retention.","evidence":"SMG7-null cells, SMG7-RAD17 Co-IP, chromatin fractionation, CHK1/RPA32 phosphorylation and DNA fiber assays","pmids":["33820915"],"confidence":"Medium","gaps":["Direct vs. bridged RAD17 contact not structurally resolved","Integration with p53/Mdm2 DDR function unclear"]},{"year":2024,"claim":"Began mapping the upstream assembly architecture by identifying UPF2 as a cross-link bridge between SMG1 and SMG7, with SMG7 contacts arising from connecting loops.","evidence":"Chemical cross-linking mass spectrometry and structural modelling","pmids":["38542156"],"confidence":"Low","gaps":["Single cross-linking MS study without orthogonal validation","Functional consequence of the UPF2-SMG7 bridge untested","No high-resolution structure of the assembly"]},{"year":null,"claim":"How SMG7 mechanistically reconciles a phosphoserine-binding adaptor activity with the phospho-independent functions revealed by K66E, and what molecular signal licenses SMG6 endonucleolysis, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Licensing signal for SMG6 not identified","Structural basis of phospho-independent UPF1/p53 binding unknown","Mechanistic link between NMD and DDR roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,4,5,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,13]}],"complexes":["SMG5-SMG7 heterodimer"],"partners":["SMG5","UPF1","UPF2","SMG1","PP2A","MDM2","P53","RAD17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92540","full_name":"Nonsense-mediated mRNA decay factor SMG7","aliases":["SMG-7 homolog","hSMG-7"],"length_aa":1137,"mass_kda":127.3,"function":"Plays a role in nonsense-mediated mRNA decay. Recruits UPF1 to cytoplasmic mRNA decay bodies. Together with SMG5 is thought to provide a link to the mRNA degradation machinery involving exonucleolytic pathways, and to serve as an adapter for UPF1 to protein phosphatase 2A (PP2A), thereby triggering UPF1 dephosphorylation","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92540/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMG7","classification":"Not Classified","n_dependent_lines":615,"n_total_lines":1208,"dependency_fraction":0.5091059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DAD1","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"UPF1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SMG7","total_profiled":1310},"omim":[{"mim_id":"610964","title":"SMG7 NONSENSE-MEDIATED mRNA DECAY FACTOR; SMG7","url":"https://www.omim.org/entry/610964"},{"mim_id":"610963","title":"SMG6 NONSENSE-MEDIATED mRNA DECAY FACTOR; SMG6","url":"https://www.omim.org/entry/610963"},{"mim_id":"610962","title":"SMG5 NONSENSE-MEDIATED mRNA DECAY FACTOR; SMG5","url":"https://www.omim.org/entry/610962"},{"mim_id":"608701","title":"NICOTINAMIDE NUCLEOTIDE ADENYLYLTRANSFERASE 2; NMNAT2","url":"https://www.omim.org/entry/608701"},{"mim_id":"601430","title":"UPF1 RNA HELICASE AND ATPase; UPF1","url":"https://www.omim.org/entry/601430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMG7"},"hgnc":{"alias_symbol":["KIAA0250","EST1C","SGA56M","SMG-7"],"prev_symbol":["C1orf16"]},"alphafold":{"accession":"Q92540","domains":[{"cath_id":"1.25.40.10","chopping":"2-123_138-183","consensus_level":"medium","plddt":91.4198,"start":2,"end":183}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92540","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92540-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92540-F1-predicted_aligned_error_v6.png","plddt_mean":58.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMG7","jax_strain_url":"https://www.jax.org/strain/search?query=SMG7"},"sequence":{"accession":"Q92540","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92540.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92540/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92540"}},"corpus_meta":[{"pmid":"15721257","id":"PMC_15721257","title":"SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15721257","citation_count":193,"is_preprint":false},{"pmid":"27864472","id":"PMC_27864472","title":"Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27864472","citation_count":157,"is_preprint":false},{"pmid":"12554878","id":"PMC_12554878","title":"Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1.","date":"2003","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12554878","citation_count":135,"is_preprint":false},{"pmid":"9927455","id":"PMC_9927455","title":"smg-7 is required for mRNA surveillance in Caenorhabditis elegans.","date":"1999","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9927455","citation_count":104,"is_preprint":false},{"pmid":"25013172","id":"PMC_25013172","title":"Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25013172","citation_count":90,"is_preprint":false},{"pmid":"23348841","id":"PMC_23348841","title":"An unusual arrangement of two 14-3-3-like domains in the SMG5-SMG7 heterodimer is required for efficient nonsense-mediated mRNA decay.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23348841","citation_count":79,"is_preprint":false},{"pmid":"34172724","id":"PMC_34172724","title":"SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity.","date":"2021","source":"Nature 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29348139","citation_count":27,"is_preprint":false},{"pmid":"31519907","id":"PMC_31519907","title":"UPF1/SMG7-dependent microRNA-mediated gene regulation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31519907","citation_count":26,"is_preprint":false},{"pmid":"27462439","id":"PMC_27462439","title":"SMG7 is a critical regulator of p53 stability and function in DNA damage stress response.","date":"2016","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27462439","citation_count":24,"is_preprint":false},{"pmid":"21234790","id":"PMC_21234790","title":"Functional analysis of the grapevine paralogs of the SMG7 NMD factor using a heterolog VIGS-based gene depletion-complementation system.","date":"2011","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21234790","citation_count":15,"is_preprint":false},{"pmid":"26783109","id":"PMC_26783109","title":"Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production.","date":"2016","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26783109","citation_count":11,"is_preprint":false},{"pmid":"32602581","id":"PMC_32602581","title":"Nonsense-mediated decay factor SMG7 sensitizes cells to TNFα-induced apoptosis via CYLD tumor suppressor and the noncoding oncogene Pvt1.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32602581","citation_count":10,"is_preprint":false},{"pmid":"34954877","id":"PMC_34954877","title":"The cap-snatching frequency of a plant bunyavirus from nonsense mRNAs is low but is increased by silencing of UPF1 or SMG7.","date":"2021","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34954877","citation_count":8,"is_preprint":false},{"pmid":"37349371","id":"PMC_37349371","title":"Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37349371","citation_count":5,"is_preprint":false},{"pmid":"31511540","id":"PMC_31511540","title":"Characterization of SMG7 14-3-3-like domain reveals phosphoserine binding-independent regulation of p53 and UPF1.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31511540","citation_count":5,"is_preprint":false},{"pmid":"35511739","id":"PMC_35511739","title":"SNPs at SMG7 Associated with Time from Biochemical Recurrence to Prostate Cancer Death.","date":"2022","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35511739","citation_count":4,"is_preprint":false},{"pmid":"33820915","id":"PMC_33820915","title":"Critical role of SMG7 in activation of the ATR-CHK1 axis in response to genotoxic stress.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33820915","citation_count":3,"is_preprint":false},{"pmid":"38542156","id":"PMC_38542156","title":"In Vitro Cross-Linking MS Reveals SMG1-UPF2-SMG7 Assembly as Molecular Partners within the NMD Surveillance.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38542156","citation_count":3,"is_preprint":false},{"pmid":"42014707","id":"PMC_42014707","title":"SMG7 and eIF4A constitute a homeostatic module controlling P-body condensation and function of meiotic bodies.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42014707","citation_count":0,"is_preprint":false},{"pmid":"42249515","id":"PMC_42249515","title":"Neural SMG7 deficiency induces autism-like behaviours via PKD1 upregulation.","date":"2026","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/42249515","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.25.690347","title":"Ferrapoptosis: Discovery of a Hybrid Programmed Cell Death","date":"2025-11-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.690347","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13610,"output_tokens":4015,"usd":0.050528,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11701,"output_tokens":4532,"usd":0.085903,"stage2_stop_reason":"end_turn"},"total_usd":0.136431,"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\": 2005,\n      \"finding\": \"Crystal structure of the N-terminal domain of SMG7 reveals a 14-3-3-like domain. Residues equivalent to phosphoserine-binding residues in canonical 14-3-3 proteins are conserved in SMG7 and mediate binding to phosphorylated UPF1. Mutation of these residues impairs UPF1 binding to SMG7 in vitro and UPF1 recruitment to cytoplasmic mRNA decay foci in vivo, establishing SMG7 as a phospho-adaptor that targets mRNAs associated with phosphorylated UPF1 for degradation.\",\n      \"method\": \"X-ray crystallography, in vitro binding assay with phosphoserine mutants, in vivo localization (mRNA decay foci)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validated both in vitro and in vivo, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"15721257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human SMG7 (hSmg5/7a) copurifies with UPF1, UPF2, UPF3X, SMG1, and the catalytic subunit of protein phosphatase 2A (PP2A), and functions in dephosphorylation of UPF1 but not UPF2, indicating that SMG7 targets PP2A to UPF1. SMG7 is predominantly cytoplasmic in HEK293T cells.\",\n      \"method\": \"Co-purification/Co-IP, dephosphorylation assay, subcellular fractionation/Western blot\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-purification with functional dephosphorylation assay in single lab, two orthogonal methods\",\n      \"pmids\": [\"12554878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"C. elegans smg-7 is required for nonsense-mediated mRNA decay; null alleles of smg-7 confer temperature-sensitive stabilization of nonsense mutant mRNAs, establishing smg-7 as an essential NMD factor in vivo.\",\n      \"method\": \"Genetic screen, cloning, null allele analysis, mRNA stability assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans ortholog with mRNA stability readout, single lab\",\n      \"pmids\": [\"9927455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the C. elegans SMG5-SMG7 complex shows the two 14-3-3-like domains heterodimerize in an unusual perpendicular back-to-back orientation. Structure-based mutants confirm the heterodimer interface is conserved and essential for efficient NMD in human cells. Heterodimerization increases the affinity of the SMG5-SMG7 complex for phosphorylated UPF1, and the degradative activity of the SMG5-SMG7 complex resides specifically in SMG7.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, NMD functional assay in human cells, binding affinity measurements\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with structure-based mutagenesis validated by functional assays in human cells, multiple orthogonal methods\",\n      \"pmids\": [\"23348841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In vitro reconstitution with purified components shows that a short C-terminal segment of phosphorylated UPF1 containing the last two Ser-Gln motifs is recognized by the SMG5-SMG7 heterodimer of 14-3-3-like proteins. SMG5 and SMG7 form a heterodimer, whereas the SMG6 14-3-3-like domain is monomeric. The dominant SMG6-UPF1 interaction is phosphorylation-independent, establishing that SMG5-SMG7 and SMG6 have distinct, non-overlapping modes of UPF1 recognition.\",\n      \"method\": \"In vitro reconstitution with purified components, crystal structure of SMG6 14-3-3-like domain, binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components plus crystal structure and binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"25013172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SMG6 and SMG7 act on essentially the same endogenous NMD target transcripts, indicating extensive redundancy between the endonucleolytic (SMG6) and exonucleolytic (SMG7) decay routes. NMD target features include introns in 3' UTRs, upstream ORFs, and long 3' UTRs.\",\n      \"method\": \"Transcriptome profiling of knockdowns and rescues of UPF1, SMG6, and SMG7; meta-analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide knockdown/rescue in human cells, single lab with combinatorial approach\",\n      \"pmids\": [\"27864472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SMG7 is a novel p53-binding protein that promotes DNA damage-induced p53 stabilization. SMG7 knockout abrogates DNA damage-induced p53 stabilization and impairs p53-mediated p21 activation and cell cycle arrest. SMG7 physically interacts with Mdm2 and promotes ATM-mediated inhibitory phosphorylation of Mdm2 following ionizing radiation, thereby preventing Mdm2-mediated p53 degradation.\",\n      \"method\": \"Somatic gene knockout, Co-IP (SMG7-p53 and SMG7-Mdm2), Mdm2 phosphorylation assay, cell cycle analysis\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — somatic KO with defined phenotype plus Co-IP and phosphorylation assay, single lab\",\n      \"pmids\": [\"27462439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of the SMG5-SMG7 pathway also inactivates the SMG6 endonucleolytic branch, demonstrating an unexpected functional dependency. Either SMG5 or SMG7 alone is sufficient to support SMG6-mediated endonucleolysis of NMD targets, establishing a two-factor authentication model where UPF1 phosphorylation and SMG5-SMG7 recruitment are both required to access SMG6 activity.\",\n      \"method\": \"siRNA depletion of SMG5 and SMG7, transcriptome-wide analysis, functional NMD assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide depletion with functional assays, single lab, multiple methods\",\n      \"pmids\": [\"34172724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SMG7 interacts with SMG5 but not with PNRC2; PNRC2 preferentially complexes with SMG5. Tethering experiments show that SMG6 is required for UPF1-mediated efficient mRNA degradation. SMG5/SMG7-dependent NMD substrates show less overlap with PNRC2-dependent NMD substrates, suggesting partial segregation of NMD pathways.\",\n      \"method\": \"Co-IP, microarray analysis, tethering assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with microarray and tethering assays, single lab\",\n      \"pmids\": [\"23234702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SMG7 interacts with SMG5 (confirmed by Co-IP), and this SMG5-SMG7 complex is functionally required for NMD. In contrast, no physical or functional interaction between SMG5 and PNRC2 was detected. UPF1 interacts with PNRC2 and triggers 5'-3' exonucleolytic decay in tethering assays; PNRC2 knockdown does not affect NMD reporter RNA levels, indicating PNRC2 is not required for NMD.\",\n      \"method\": \"Co-IP, tethering assay, siRNA knockdown, NMD reporter assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP combined with functional tethering and knockdown assays, single lab\",\n      \"pmids\": [\"29348139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast Ebs1p, identified as the putative S. cerevisiae ortholog of human SMG7, physically interacts with the NMD helicase Upf1p. Overexpressed Ebs1p recruits Upf1p into cytoplasmic P-bodies, and Ebs1p itself localizes to P-bodies upon glucose starvation. Both loss and overexpression of Ebs1p stabilize NMD targets.\",\n      \"method\": \"Sequence alignment, Co-IP, fluorescence microscopy (P-body localization), mRNA stability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization with functional NMD assay, single lab, yeast ortholog\",\n      \"pmids\": [\"17984081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SMG7 interacts with the CCR4-NOT deadenylase complex, and loss of the SMG7-deadenylase complex interaction increases the levels of transcripts regulated by UPF1-SMG7. In combination with Ago2 and UPF1, SMG7 mediates miRNA-targeted mRNA degradation in a 3'UTR-length-dependent manner.\",\n      \"method\": \"Co-IP (Ago2-UPF1-SMG7), siRNA knockdown, RNA-seq, reporter assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP combined with knockdown and transcriptome analysis, single lab\",\n      \"pmids\": [\"31519907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNA damage-induced SMG7-p53 binding requires phosphorylated Ser15 on p53. Substitution of conserved lysine K66 in the SMG7 14-3-3-like domain with glutamic acid (K66E) abolishes interactions with p53 and UPF1 in vitro. Unexpectedly, cells expressing SMG7 K66E retain p53 stabilization/activation and fully functional NMD, indicating that phosphoserine-dependent SMG7 binding is not the sole or essential mechanism for these functions.\",\n      \"method\": \"Knockin mutagenesis (K66E), co-IP, cell cycle and apoptosis assays, NMD reporter assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockin mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"31511540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMG7 is required for ATR-CHK1 axis activation upon genotoxic stress. SMG7-null cells exhibit attenuated phosphorylation of CHK1 and RPA32 and unhindered DNA replication after damage. Through its 14-3-3 domain, SMG7 directly interacts with Ser635-phosphorylated RAD17 and promotes chromatin retention of the 9-1-1 complex by RAD17-RFC, an essential step for CHK1 activation. SMG7 also controls G2-M transition and facilitates cell cycle recovery from replication stress.\",\n      \"method\": \"SMG7-null cells, Co-IP (SMG7-RAD17), chromatin fractionation, CHK1/RPA32 phosphorylation assay, DNA fiber assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined signaling phenotype plus Co-IP and chromatin fractionation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33820915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chemical cross-linking mass spectrometry (CLMS) identifies protein-protein interactions among SMG1, UPF2, and SMG7, revealing UPF2 as a bridging protein between SMG1 and SMG7. The UPF2 N-terminal region mediates most interactions with SMG7, while SMG7 interactions emerge predominantly from connecting loops rather than well-defined secondary structures.\",\n      \"method\": \"Chemical cross-linking mass spectrometry (CLMS), structural modelling\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cross-linking MS study without orthogonal validation, single lab\",\n      \"pmids\": [\"38542156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMG7 is a 14-3-3-like adaptor protein that, as part of a heterodimer with SMG5, recognizes phosphorylated UPF1 (at C-terminal Ser-Gln motifs phosphorylated by SMG1) to recruit the PP2A phosphatase for UPF1 dephosphorylation and to channel NMD target mRNAs into exonucleolytic decay; SMG7's degradative activity also requires interaction with the CCR4-NOT deadenylase complex, and its presence is required to authorize SMG6-mediated endonucleolytic cleavage, making SMG5-SMG7 an essential upstream licensing factor for both NMD degradation branches. Beyond NMD, SMG7 also functions in the DNA damage response by binding phospho-Ser15-p53, interacting with Mdm2 to promote ATM-mediated inhibitory Mdm2 phosphorylation and p53 stabilization, and by binding phospho-Ser635-RAD17 through its 14-3-3 domain to promote chromatin retention of the 9-1-1 complex and activate ATR-CHK1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMG7 is an essential nonsense-mediated mRNA decay (NMD) factor that operates as a phosphoserine-binding adaptor through an N-terminal 14-3-3-like domain, channeling aberrant transcripts marked by phosphorylated UPF1 into degradation [#0, #2]. Its 14-3-3-like domain conserves canonical phosphoserine-binding residues that recognize the C-terminal Ser-Gln motifs of UPF1 phosphorylated by SMG1, and mutation of these residues impairs UPF1 binding and recruitment to cytoplasmic mRNA decay foci [#0, #4]. SMG7 heterodimerizes with SMG5 via a perpendicular back-to-back arrangement of their 14-3-3-like domains; this dimerization raises affinity for phosphorylated UPF1, and the degradative activity of the complex resides specifically in SMG7 [#3, #4]. SMG7 co-purifies with UPF1/UPF2/UPF3X/SMG1 and the PP2A catalytic subunit, targeting PP2A to dephosphorylate UPF1 [#1], while its degradative output requires interaction with the CCR4-NOT deadenylase complex [#11]. SMG5-SMG7 and the endonuclease SMG6 act on largely the same NMD targets, and loss of SMG5-SMG7 inactivates the SMG6 branch, establishing SMG5-SMG7 as an upstream licensing factor required to authorize both decay routes [#5, #7]. Beyond NMD, SMG7 functions in the DNA damage response: it binds phospho-Ser15-p53 and Mdm2 to promote ATM-mediated inhibitory Mdm2 phosphorylation and p53 stabilization [#6], and through its 14-3-3 domain binds phospho-Ser635-RAD17 to promote chromatin retention of the 9-1-1 complex and activate ATR-CHK1 signaling [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that smg-7 is a genuine, genetically essential component of NMD in vivo, before any molecular mechanism was known.\",\n      \"evidence\": \"Genetic screen and null-allele mRNA-stability analysis in C. elegans\",\n      \"pmids\": [\"9927455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity or biochemical partners defined\", \"Ortholog system; human function not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved how SMG7 connects to the decay machinery by showing it co-purifies with UPF1/2/3, SMG1 and PP2A and directs UPF1 dephosphorylation, positioning it as a PP2A-targeting adaptor.\",\n      \"evidence\": \"Co-purification/Co-IP, dephosphorylation assay, subcellular fractionation in human cells\",\n      \"pmids\": [\"12554878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect PP2A recruitment not separated\", \"Structural basis of UPF1 recognition unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the molecular basis of target recognition by revealing a 14-3-3-like domain whose conserved phosphoserine-binding residues mediate phospho-UPF1 binding and recruitment to decay foci.\",\n      \"evidence\": \"X-ray crystallography with phosphoserine-mutant binding and in vivo localization\",\n      \"pmids\": [\"15721257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address SMG5 partnership\", \"Did not resolve downstream degradation enzymology\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked SMG7 function to P-body-associated decay by showing the yeast ortholog Ebs1p binds Upf1p and recruits it to P-bodies, with both loss and excess stabilizing NMD targets.\",\n      \"evidence\": \"Co-IP, P-body fluorescence microscopy, mRNA stability in S. cerevisiae\",\n      \"pmids\": [\"17984081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog assignment based on sequence; human conservation untested here\", \"Mechanism of biphasic loss/overexpression effect unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished SMG5-SMG7 from PNRC2-dependent routes, showing SMG7 partners SMG5 and that SMG6 is required for efficient UPF1-mediated degradation, indicating segregated decay sub-pathways.\",\n      \"evidence\": \"Co-IP, microarray, tethering assays in human cells\",\n      \"pmids\": [\"23234702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of pathway overlap unresolved\", \"Mechanistic basis of substrate segregation unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural logic of the SMG5-SMG7 complex, showing perpendicular heterodimerization of 14-3-3-like domains that boosts phospho-UPF1 affinity and localizing degradative activity to SMG7.\",\n      \"evidence\": \"Crystal structure of C. elegans SMG5-SMG7 with structure-based mutagenesis validated in human NMD assays\",\n      \"pmids\": [\"23348841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of effector engaged by SMG7's degradative region not defined\", \"Human complex structure not solved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstituted recognition in vitro, defining that SMG5-SMG7 binds a short phospho-UPF1 segment via two Ser-Gln motifs while monomeric SMG6 uses a phosphorylation-independent mode, establishing distinct non-overlapping UPF1 engagement.\",\n      \"evidence\": \"In vitro reconstitution with purified components, SMG6 14-3-3 crystal structure, binding assays\",\n      \"pmids\": [\"25013172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell coordination of the two recognition modes not addressed\", \"Kinetics of handoff to decay enzymes unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the transcriptome-scale division of labor, showing SMG6 and SMG7 act on essentially the same NMD targets, implying redundant endo- and exonucleolytic routes.\",\n      \"evidence\": \"Transcriptome profiling of UPF1/SMG6/SMG7 knockdown-rescue\",\n      \"pmids\": [\"27864472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish hierarchical dependency between branches\", \"Target-feature determinants of branch choice unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended SMG7 function beyond NMD by identifying it as a p53-binding protein required for DNA-damage-induced p53 stabilization via Mdm2 interaction and ATM-mediated Mdm2 phosphorylation.\",\n      \"evidence\": \"Somatic knockout, SMG7-p53 and SMG7-Mdm2 Co-IP, Mdm2 phosphorylation and cell-cycle assays\",\n      \"pmids\": [\"27462439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. scaffolded effect on ATM-Mdm2 not separated\", \"Relationship between NMD and DDR roles unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SMG7 degradative output to a specific effector by showing it binds CCR4-NOT and contributes to Ago2/UPF1-dependent miRNA-targeted mRNA decay in a 3'UTR-length-dependent manner.\",\n      \"evidence\": \"Co-IP (Ago2-UPF1-SMG7), siRNA knockdown, RNA-seq, reporter assays\",\n      \"pmids\": [\"31519907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CCR4-NOT contact residues not mapped\", \"Generality across NMD targets vs. miRNA targets unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested whether phosphoserine binding is the essential mechanism, finding the 14-3-3 K66E mutant abolishes p53/UPF1 binding in vitro yet cells retain p53 activation and functional NMD, revealing phospho-independent contributions.\",\n      \"evidence\": \"K66E knockin mutagenesis with NMD reporter, cell cycle and apoptosis assays\",\n      \"pmids\": [\"31511540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alternative binding surfaces or redundant factors not identified\", \"Reconciliation with strict phospho-dependence seen in vitro unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the obligate SMG5-SMG7 partnership for NMD while excluding a functional SMG5-PNRC2 axis, clarifying which interactions are necessary for decay.\",\n      \"evidence\": \"Reciprocal Co-IP, tethering, siRNA knockdown, NMD reporter assays\",\n      \"pmids\": [\"29348139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PNRC2's role in any subset of substrates not fully excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed branch redundancy into a licensing hierarchy by showing loss of SMG5-SMG7 inactivates the SMG6 endonucleolytic branch, with either SMG5 or SMG7 sufficient — a two-factor authentication model for accessing SMG6.\",\n      \"evidence\": \"siRNA depletion of SMG5/SMG7, transcriptome-wide and functional NMD assays\",\n      \"pmids\": [\"34172724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signal that authorizes SMG6 not identified\", \"Whether dephosphorylation or recruitment is the licensing trigger unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a second DDR role, showing SMG7 is required for ATR-CHK1 activation by binding phospho-Ser635-RAD17 through its 14-3-3 domain and promoting 9-1-1 chromatin retention.\",\n      \"evidence\": \"SMG7-null cells, SMG7-RAD17 Co-IP, chromatin fractionation, CHK1/RPA32 phosphorylation and DNA fiber assays\",\n      \"pmids\": [\"33820915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. bridged RAD17 contact not structurally resolved\", \"Integration with p53/Mdm2 DDR function unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Began mapping the upstream assembly architecture by identifying UPF2 as a cross-link bridge between SMG1 and SMG7, with SMG7 contacts arising from connecting loops.\",\n      \"evidence\": \"Chemical cross-linking mass spectrometry and structural modelling\",\n      \"pmids\": [\"38542156\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single cross-linking MS study without orthogonal validation\", \"Functional consequence of the UPF2-SMG7 bridge untested\", \"No high-resolution structure of the assembly\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMG7 mechanistically reconciles a phosphoserine-binding adaptor activity with the phospho-independent functions revealed by K66E, and what molecular signal licenses SMG6 endonucleolysis, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Licensing signal for SMG6 not identified\", \"Structural basis of phospho-independent UPF1/p53 binding unknown\", \"Mechanistic link between NMD and DDR roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"complexes\": [\"SMG5-SMG7 heterodimer\"],\n    \"partners\": [\"SMG5\", \"UPF1\", \"UPF2\", \"SMG1\", \"PP2A\", \"Mdm2\", \"p53\", \"RAD17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}