Affinage

SMG6

Telomerase-binding protein EST1A · UniProt Q86US8

Length
1419 aa
Mass
160.5 kDa
Annotated
2026-06-10
29 papers in source corpus 21 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMG6 is the metazoan-specific endonuclease of the nonsense-mediated mRNA decay (NMD) pathway, cleaving mRNAs near premature termination codons through its C-terminal PIN domain and thereby acting as a central effector of cytoplasmic mRNA surveillance and post-transcriptional gene regulation (PMID:17053788, PMID:19060897). Its PIN domain carries the canonical acidic catalytic triad of an RNase H-like nuclease, and active-site mutagenesis abolishes endonucleolysis while a domain swap with an unrelated endonuclease rescues NMD, establishing that the sole function of the SMG6 PIN domain is to provide nuclease activity (PMID:17053788, PMID:19060897, PMID:18974281). Full catalytic activity arises from a composite active site: the PIN domain of catalytically dead SMG5 contributes a conserved aspartate that completes the SMG6 acidic tetrad, and the reconstituted SMG5-SMG6 cPIN heterodimer is markedly more active than SMG6 alone (PMID:41714610, PMID:41638882). SMG6 cleaves at a preferred sequence motif across hundreds of endogenous targets, generating metastable decay intermediates, and competes with the SMG5-SMG7-dependent exonucleolytic branch acting on largely the same transcripts (PMID:24086375, PMID:25429978, PMID:27864472). Recruitment to targets is achieved through a phosphorylation-independent short linear motif that engages the UPF1 CH domain mutually exclusively with UPF2, together with direct EJC binding via two conserved EJC-binding motifs; full endonucleolysis additionally requires prior SMG5/SMG7 engagement of phosphorylated UPF1 to license SMG6 activity (PMID:20930030, PMID:25013172, PMID:34172724, PMID:38709891). Beyond surveillance, SMG6 nuclease function governs embryonic stem cell differentiation through decay of pluripotency transcripts such as c-Myc, sets the mammalian circadian period via decay of Cry2 mRNA, is required for male germ cell differentiation where it localizes to the chromatoid body with PIWIL1, and is essential for organogenesis and adult tissue homeostasis (PMID:25770585, PMID:36259644, PMID:36638184, PMID:41677645). SMG6 also associates with telomerase through both hTR RNA binding and direct hTERT protein contacts (PMID:17940095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2006 High

    Whether the NMD machinery contains an intrinsic ribonuclease was unknown; structural and biochemical comparison of the SMG5 and SMG6 PIN domains located catalytic potential specifically in SMG6.

    Evidence X-ray crystallography of human SMG5/SMG6 PIN domains with in vitro ssRNA degradation and a dominant-negative PIN mutant in Drosophila

    PMID:17053788

    Open questions at the time
    • Did not show SMG6 cleaves PTC-containing mRNAs in cells
    • Did not define recruitment to targets
  2. 2007 Medium

    High-resolution structure detailed the SMG6 PIN fold, confirming an RNase H/5' nuclease-like architecture with invariant acidic active-center residues.

    Evidence X-ray crystallography of the human EST1A/SMG6 PIN domain at 1.8 Å

    PMID:17557331

    Open questions at the time
    • No functional mutagenesis in this study
    • Catalytic mechanism inferred from geometry only
  3. 2007 Medium

    Established a telomerase association for SMG6 distinct from its NMD role, mapping both an RNA-mediated (hTR) and a direct protein-protein (hTERT) contact.

    Evidence In vitro binding assays with purified recombinant hEST1A, RNase treatment to separate RNA- vs protein-mediated contacts, and affinity measurements

    PMID:17940095

    Open questions at the time
    • Functional consequence for telomere maintenance not established
    • Single-lab in vitro binding only
  4. 2008 High

    Resolved the identity of the PTC-proximal NMD endonuclease, demonstrating that SMG6 catalyzes the cleavage and that the PIN domain's sole role is nuclease activity.

    Evidence Active-site mutagenesis, in vitro endonuclease assay, PIN domain-swap rescue and NMD reporters in human and Drosophila cells (two independent studies)

    PMID:18974281 PMID:19060897

    Open questions at the time
    • Did not define how SMG6 is recruited to targets
    • Did not address the SMG5-SMG7 exonucleolytic branch relationship
  5. 2010 High

    Addressed how the endonuclease reaches its targets, showing the EJC recruits SMG6 via two conserved EJC-binding motifs required for NMD.

    Evidence Sequence identification of EBMs, direct binding assays, EBM mutagenesis and NMD reporter assays

    PMID:20930030

    Open questions at the time
    • Relationship between EJC binding and UPF1 binding not resolved
    • Did not determine timing of recruitment relative to UPF1 phosphorylation
  6. 2012 Medium

    Revealed that SMG6 contributes to NMD beyond catalysis, distinguishing endonucleolytic from non-endonucleolytic functions genetically.

    Evidence Forward genetic mosaic screen and characterization of Drosophila Smg6 point mutants with NMD target analysis

    PMID:22740637

    Open questions at the time
    • Molecular basis of the non-nuclease role undefined
    • Drosophila-specific; not mapped to a domain
  7. 2013 Medium

    Confirmed in a defined endogenous substrate that SMG6 endonucleolysis generates metastable 5'-truncated decay intermediates.

    Evidence siRNA knockdown with siRNA-resistant wild-type and PIN-mutant rescue and qRT-PCR in inducible erythroid cells (nonsense β-globin)

    PMID:24086375

    Open questions at the time
    • Single reporter transcript
    • Did not map cleavage at nucleotide resolution
  8. 2014 High

    Defined SMG6 cleavage specificity transcriptome-wide and revealed competition between endonucleolytic and exonucleolytic NMD routes.

    Evidence PARE mapping of decay-intermediate 5' termini, SMG6/UPF1 depletion and mutational validation of the cleavage motif in human cells

    PMID:25429978

    Open questions at the time
    • Determinants selecting endo- vs exonucleolytic route per transcript unclear
  9. 2014 High

    Defined the dominant SMG6-UPF1 contact as phosphorylation-independent, distinct from the phospho-dependent SMG5-SMG7 mode of UPF1 recognition.

    Evidence Crystal structure of the SMG6 14-3-3-like domain plus in vitro reconstitution and binding to phosphorylated/unphosphorylated UPF1 fragments; complementary tethering and domain-binding assays

    PMID:25013172 PMID:25053839

    Open questions at the time
    • Precise SMG6 motif on UPF1 stalk not fully resolved here
    • Coordination with EJC binding unaddressed
  10. 2015 High

    Established a physiological developmental role, showing SMG6/NMD licenses ESC differentiation by clearing pluripotency transcripts including c-Myc.

    Evidence Smg6 knockout and inducible deletion mice, ESC differentiation assays, c-Myc forced downregulation rescue and iPSC reprogramming assays

    PMID:25770585

    Open questions at the time
    • Did not separate nuclease from non-nuclease contributions
    • Full set of relevant NMD targets not delineated
  11. 2016 Medium

    Quantified redundancy between the SMG6 endonucleolytic and SMG7 exonucleolytic routes, showing they act on essentially the same target set.

    Evidence RNA-seq of single and combined knockdown/rescue of UPF1, SMG6 and SMG7 in human cells

    PMID:27864472

    Open questions at the time
    • Mechanism of route selection unresolved
    • Single-lab transcriptome analysis
  12. 2021 High

    Revealed an unexpected dependency in which SMG5-SMG7 recruitment to phosphorylated UPF1 is required to authorize SMG6 endonucleolysis.

    Evidence RNA-seq with combinatorial SMG5/SMG7/SMG6 depletion and PARE-seq cleavage-site detection

    PMID:34172724

    Open questions at the time
    • Molecular step by which SMG5/SMG7 licenses SMG6 not structurally defined here
  13. 2022 High

    Extended SMG6 function to spermatogenesis, showing it is required for male germ cell differentiation and localizes to the chromatoid body with PIWIL1.

    Evidence Germ-cell conditional Smg6 knockout mice, RNA-seq, immunofluorescence localization and comparison with Piwil1-KO

    PMID:36259644

    Open questions at the time
    • Mechanistic link between SMG6 and PIWIL1 co-regulation undefined
    • Direct germ-cell NMD targets not fully resolved
  14. 2022 Medium

    Showed therapeutic relevance: specific nonsense CFTR mRNAs are degraded preferentially by the SMG6 endonucleolytic branch rather than the SMG5-SMG7 route.

    Evidence Antisense oligonucleotide knockdown of individual NMD factors with CFTR mRNA quantification across multiple PTC alleles

    PMID:35487895

    Open questions at the time
    • Allele-specific basis for branch preference unexplained
    • Single-lab study
  15. 2023 High

    Demonstrated that SMG6 nuclease activity sets the mammalian circadian period through decay of the clock repressor transcript Cry2.

    Evidence Conditional nuclease-dead SMG6 knock-in mice, in vivo circadian period measurement, RNA-seq and Cry2 target identification

    PMID:36638184

    Open questions at the time
    • Whether Cry2 alone accounts for the period phenotype not fully established
  16. 2024 High

    Defined the structural basis of SMG6 recruitment via a SLiM-CH domain contact that is mutually exclusive with UPF2 binding to UPF1.

    Evidence Mass spectrometry, cryo-EM, biochemical binding assays with purified components and SLiM mutagenesis

    PMID:38709891

    Open questions at the time
    • Conformational triggers switching UPF1 between UPF2- and SMG6-bound states not defined
  17. 2026 High

    Resolved how full catalytic activity is achieved, showing SMG5 PIN completes the SMG6 acidic tetrad to form a composite active site with ~10-fold enhanced endonuclease activity.

    Evidence AlphaFold prediction validated by in vitro reconstitution, interface/active-site/RNA-binding mutagenesis, cell-based NMD reporters, and C. elegans pulldowns with compensatory salt-bridge mutagenesis

    PMID:41638882 PMID:41714610

    Open questions at the time
    • Experimental high-resolution structure of the cPIN heterodimer not reported
    • Stoichiometry and assembly timing on target mRNA undefined
  18. 2026 High

    Separated nuclease from non-nuclease functions in vivo, showing the SMG6 PIN endoribonuclease activity is essential for NMD, ESC differentiation, organogenesis and adult tissue homeostasis.

    Evidence Conditional PIN-domain-inactivating (Smg6-PINF/F) mouse model with ESC differentiation, tissue-specific and NMD activity assays

    PMID:41677645

    Open questions at the time
    • Scope of non-nuclease functions in vivo not delineated
    • Tissue-specific target sets not enumerated
  19. 2025 Medium

    Linked SMG6-dependent NMD to innate immune homeostasis, showing its loss causes cytoplasmic dsRNA accumulation and MDA5-driven type I interferon induction.

    Evidence Liver-specific inducible SMG6 inactivation in an HCC mouse model with dsRNA detection and MDA5/interferon pathway analysis (preprint)

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Identity of the dsRNA species and direct NMD targets not defined
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How recruitment cues (EJC binding, UPF1 SLiM-CH contact, SMG5-SMG7 licensing) are temporally integrated to trigger composite-active-site assembly and cleavage on a given target remains unresolved.
  • No integrated structural model of the assembled, RNA-engaged SMG5-SMG6 endonuclease complex
  • Determinants of endo- vs exonucleolytic route selection per transcript unknown
  • Mechanism of non-nuclease SMG6 functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9909396 Circadian clock 1
Partners
HTERTPIWIL1SMG5SMG7UPF1UPF2
Complex memberships
SMG5-SMG6 composite PIN (cPIN) heterodimerchromatoid bodyexon junction complex (EJC)-associated NMD complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structures of human SMG5 and SMG6 PIN domains revealed that SMG6 has the canonical triad of acidic residues required for RNase H-like nuclease activity, while SMG5 lacks key catalytic residues. Only the PIN domain of SMG6 showed degradation activity on single-stranded RNA in vitro, establishing intrinsic nuclease activity within the NMD machinery. X-ray crystallography of PIN domains; in vitro ssRNA degradation assay; dominant-negative SMG6 PIN mutant in Drosophila NMD assay The EMBO journal High 17053788
2007 Crystal structure of the PIN domain of human EST1A/SMG6 at 1.8 Å resolution revealed an α/β fold similar to 5′ nucleases and RNase H, with an extended region absent from archaeal PIN-domain proteins; the putative active center contains invariant acidic residues geometrically similar to 5′ nucleases. X-ray crystallography at 1.8 Å resolution Proteins Medium 17557331
2007 SMG6/hEST1A interacts with telomerase through both protein-RNA and protein-protein contacts: a domain within hEST1A binds the telomerase RNA moiety hTR with high affinity (apparent Kd ~25 nM), and full-length hEST1A also forms RNase-resistant, hTR-independent protein-protein contacts with hTERT. Within hTERT, a domain was identified that harbors both hTR-binding activity and RNA-independent hEST1A-binding activity. In vitro binding assays with purified recombinant hEST1A; RNase treatment to distinguish RNA-mediated vs. direct protein-protein contacts; affinity measurements Nucleic acids research Medium 17940095
2008 SMG6 is the endonuclease responsible for PTC-proximal mRNA cleavage during NMD in human cells. Mutation of conserved acidic residues in the PIN domain abolished endonucleolysis both in vivo and in vitro. Furthermore, replacing the SMG6 PIN domain with the active PIN domain of an unrelated protein restored NMD, demonstrating that the sole function of the SMG6 PIN domain is to provide endonuclease activity. PIN domain active-site mutagenesis; in vitro endonuclease assay; PIN domain swap experiment; NMD reporter assays in human cells Nature structural & molecular biology High 19060897
2008 SMG6 is the conserved NMD endonuclease in metazoans: cells expressing catalytic-residue mutants of SMG6 fail to degrade PTC-containing mRNAs, and domain-swap experiments confirmed that the sole function of the SMG6 PIN domain in NMD is to provide endonuclease activity. Active-site mutagenesis of SMG6 PIN domain; PIN domain swap with unrelated endonuclease; NMD reporter assays in human and Drosophila cells RNA (New York, N.Y.) High 18974281
2010 SMG6 interacts directly with the exon junction complex (EJC) via two conserved EJC-binding motifs (EBMs) in SMG6. This SMG6-EJC interaction is required for NMD, revealing that the EJC recruits the SMG6 endonuclease to NMD targets in vertebrates. Identification of EBMs by sequence analysis; direct binding assays; mutational analysis of EBMs; NMD reporter assays with EBM mutants Genes & development High 20930030
2012 Genetic analysis of Drosophila Smg6 point mutants established that SMG6 has both endonucleolytic and non-endonucleolytic roles in NMD, indicating that SMG6 contributes to NMD through mechanisms beyond its nuclease activity. Forward genetic mosaic screen in Drosophila; isolation and characterization of Smg6 point mutations; NMD target analysis RNA (New York, N.Y.) Medium 22740637
2013 SMG6 endonuclease cleavage generates metastable 5′-truncated decay intermediates from nonsense-containing β-globin mRNA. Knockdown of SMG6 increased full-length nonsense mRNA and decreased the Δ169 decay intermediate; complementation with siRNA-resistant wild-type SMG6 but not PIN-domain-inactivating mutants rescued the intermediate, confirming SMG6 endonucleolytic cleavage generates these products. SMG6 knockdown with siRNA; siRNA-resistant SMG6 complementation; PIN domain mutagenesis; quantitative RT-PCR for full-length and truncated intermediates in inducible erythroid cells PloS one Medium 24086375
2014 SMG6 cleavage sites in hundreds of endogenous NMD target mRNAs in human cells were mapped at nucleotide resolution, revealing a preferred sequence motif spanning most SMG6 cleavage sites. Mutational analysis validated this motif. Depletion of SMG6 also caused accumulation of decapped transcripts, indicating competition between SMG6-dependent endonucleolytic and SMG6-independent exonucleolytic NMD pathways. Parallel Analysis of RNA Ends (PARE) to identify 5′ termini of SMG6-dependent decay intermediates; SMG6/UPF1 depletion; mutational validation of the cleavage motif Nucleic acids research High 25429978
2014 The dominant interaction between SMG6 and UPF1 is phosphorylation-independent and is mediated by a low-complexity region bordering the 14-3-3-like domain of SMG6 and the helicase domain plus C-terminal tail of UPF1. In contrast, SMG5-SMG7 recognize phosphorylated UPF1 via their 14-3-3-like heterodimer. The SMG6 14-3-3-like domain is monomeric and mediates only a weak phospho-dependent interaction with UPF1. These two modes of UPF1 recognition are distinct and non-overlapping. Crystal structure of SMG6 14-3-3-like domain; in vitro reconstitution with purified components; binding assays with phosphorylated and unphosphorylated UPF1 fragments Nucleic acids research High 25013172
2014 SMG6 requires a novel phosphorylation-independent interaction with the stalk region of the UPF1 helicase domain (along with a contribution from the SQ domain) to reduce mRNA levels. This interaction is essential for NMD and for the ability of tethered SMG6 to degrade bound RNA, suggesting it contributes to the regulation of both UPF1 and SMG6 enzymatic activities. Artificial tethering of SMG6 and mutants to reporter mRNA; knockdowns of NMD factors; in vivo and in vitro binding assays between SMG6 and UPF1 domains Nucleic acids research Medium 25053839
2015 Smg6/Est1 knockout mice die at the blastocyst stage; inducible deletion blocks ESC differentiation due to sustained expression of pluripotency genes normally repressed by NMD (including c-Myc). Forced downregulation of c-Myc relieves the differentiation block. Smg6-null embryonic fibroblasts are refractory to reprogramming into iPSCs. Depletion of all major NMD factors also compromises ESC differentiation, identifying NMD as a licensing factor for cell identity switching. Smg6 knockout mice; inducible conditional deletion; ESC differentiation assays; c-Myc forced downregulation rescue experiment; iPSC reprogramming assay The EMBO journal High 25770585
2016 Transcriptome-wide analysis combining knockdown and rescue of UPF1, SMG6, and SMG7 revealed that SMG6-mediated endonucleolytic and SMG7-mediated exonucleolytic decay routes act on essentially the same set of endogenous NMD target transcripts, demonstrating extensive functional redundancy between the two pathways. Transcriptome profiling (RNA-seq) of single and combined knockdown/rescue of NMD factors UPF1, SMG6, and SMG7 in human cells RNA (New York, N.Y.) Medium 27864472
2021 Loss of the SMG5-SMG7-dependent NMD pathway also inactivates the SMG6-dependent endonucleolytic branch, revealing an unexpected functional dependency. Either SMG5 or SMG7 alone is sufficient to support SMG6-mediated endonucleolysis of NMD targets, indicating that SMG5-SMG7 recruitment to phosphorylated UPF1 is required to authorize SMG6 activity. Transcriptome-wide analysis (RNA-seq); combinatorial depletion of SMG5, SMG7, and SMG6; PARE-seq for endonucleolytic cleavage site detection Nature communications High 34172724
2022 SMG6 is essential for male germ cell differentiation in mice: germline-conditional Smg6 knockout causes complete spermatogenesis arrest at the early haploid stage, with accumulation of NMD target mRNAs bearing long 3′ UTRs and failure to eliminate meiotically expressed transcripts. SMG6 localizes to the chromatoid body (CB) in male germ cells, co-localizing with PIWIL1; SMG6 and PIWIL1 co-regulate many genes in round spermatids. Germ-cell conditional knockout mice; RNA-seq transcriptome profiling; immunofluorescence/microscopy for SMG6 localization to chromatoid body; comparison with Piwil1-KO mice phenotype Nucleic acids research High 36259644
2022 CFTR mRNAs with nonsense codons are degraded via the SMG6-mediated endonucleolytic NMD pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway; this was demonstrated for G542X, R1162X, and W1282X but not Y122X variants. Antisense oligonucleotides targeting NMD factors (SMG6, SMG5, SMG7, UPF2, UPF3); quantification of CFTR mRNA levels; NMD pathway inhibition combined with translational readthrough therapy Nature communications Medium 35487895
2023 SMG6 PIN domain nuclease activity regulates the mammalian circadian clock: conditional conversion of SMG6 to a nuclease-dead mutant in mice caused strong lengthening of free-running circadian periods in liver and fibroblast clocks. Cry2 mRNA was identified as a direct NMD target regulated by SMG6; CRY2 is a key transcriptional repressor within the rhythm-generating feedback loop. Conditional mouse allele converting SMG6 to nuclease-domain mutant; circadian period measurement in vivo; transcriptome-wide RNA-seq for daily mRNA accumulation; NMD target identification including Cry2 Science advances High 36638184
2024 A conserved short linear motif (SLiM) in SMG6 interacts with the CH (cysteine/histidine-rich) domain of UPF1. Cryo-EM data indicate that the UPF1-SMG6 interaction is precluded when the UPF1 CH domain is engaged with UPF2, suggesting that SMG6-containing and UPF2-containing NMD complexes are mutually exclusive and may be dictated by different conformational/RNA-binding states of UPF1. Mass spectrometry; structural biology (cryo-EM); biochemical binding assays with purified components; mutagenesis of the SMG6 SLiM Nucleic acids research High 38709891
2026 SMG5 and SMG6 interact via their PIN domains to form a composite PIN (cPIN) heterodimer interface. In this composite active site, a conserved SMG5 aspartate (D893) complements the SMG6 acidic triad to reconstitute a canonical tetrad required for PIN-domain catalysis. Reconstituted SMG5-SMG6 cPIN shows ~10-fold enhanced endonucleolytic activity relative to SMG6 alone. Mutations disrupting the interface, RNA-binding sites, or active site impair or abolish cPIN activity in vitro and cellular NMD. AlphaFold structural prediction; in vitro endonuclease reconstitution assay; mutagenesis of interface and active-site residues; cell-based NMD reporter assays Nature communications High 41714610
2026 SMG5 PIN domain, previously considered catalytically inert, activates SMG6 endonucleolysis by completing its active site (composite active site model). AlphaFold-predicted SMG5-SMG6 PIN domain interaction was substantiated by in vitro pulldowns in C. elegans; compensatory salt bridge flip mutations perturbed and restored NMD function, confirming the functional SMG-5/SMG-6 PIN domain interaction. AlphaFold structural predictions; in vitro PIN domain pulldowns; compensatory mutagenesis (salt bridge flip) in C. elegans; in vivo NMD assays RNA (New York, N.Y.) Medium 41638882
2026 SMG6 PIN domain (endoribonuclease activity) is essential for NMD in vivo in mice: Smg6-PIN domain-specific inactivation (Smg6-PINF/F) abolished NMD activity in ESCs and adult tissues, compromised ESC differentiation (while self-renewal was unaffected), and caused lethality during organogenesis. Loss of NMD in adult mice affected tissue homeostasis in testis and intestine. Conditional PIN-domain-inactivating mouse model (Smg6-PINF/F); ESC differentiation assays; tissue-specific analysis; NMD activity assays Cells High 41677645
2025 SMG6 inactivation in a liver-specific HCC mouse model caused cytoplasmic accumulation of endogenous double-stranded RNAs (dsRNAs), triggering type I interferon induction via the dsRNA sensor MDA5, thereby revealing an unexpected role for SMG6-dependent NMD in maintaining cytoplasmic dsRNA homeostasis. Liver-specific inducible SMG6 inactivation in HCC mouse model; dsRNA detection; interferon response assays; MDA5 pathway analysis bioRxivpreprint Medium

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nature structural & molecular biology 333 19060897
2008 SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA (New York, N.Y.) 270 18974281
2006 Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex. The EMBO journal 170 17053788
2016 Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways. RNA (New York, N.Y.) 157 27864472
2015 Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. The EMBO journal 104 25770585
2014 Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6. Nucleic acids research 90 25013172
2014 Identification of SMG6 cleavage sites and a preferred RNA cleavage motif by global analysis of endogenous NMD targets in human cells. Nucleic acids research 90 25429978
2014 A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD. Nucleic acids research 75 25053839
2021 SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity. Nature communications 73 34172724
2010 SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay. Genes & development 69 20930030
2007 Protein RNA and protein protein interactions mediate association of human EST1A/SMG6 with telomerase. Nucleic acids research 48 17940095
2022 Cardioprotective Effect of circ_SMG6 Knockdown against Myocardial Ischemia/Reperfusion Injury Correlates with miR-138-5p-Mediated EGR1/TLR4/TRIF Inactivation. Oxidative medicine and cellular longevity 34 35126807
2018 The RNA surveillance proteins UPF1, UPF2 and SMG6 affect HIV-1 reactivation at a post-transcriptional level. Retrovirology 29 29954456
2022 CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway. Nature communications 28 35487895
2007 Crystal structure of the PIN domain of human telomerase-associated protein EST1A. Proteins 26 17557331
2024 Mechanism of circRNA_SMG6 mediating lung macrophage ECM degradation via miR-570-3p in microplastics-induced emphysema. Environment international 16 38685156
2023 A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway. Science advances 15 36638184
2012 Drosophila mutants show NMD pathway activity is reduced, but not eliminated, in the absence of Smg6. RNA (New York, N.Y.) 15 22740637
2024 UPF1 helicase orchestrates mutually exclusive interactions with the SMG6 endonuclease and UPF2. Nucleic acids research 14 38709891
2022 SMG6 localizes to the chromatoid body and shapes the male germ cell transcriptome to drive spermatogenesis. Nucleic acids research 14 36259644
2013 SMG6 cleavage generates metastable decay intermediates from nonsense-containing β-globin mRNA. PloS one 13 24086375
2022 SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma. Cell death discovery 9 36335095
2021 Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis. Cells 9 34943873
2018 SRR intronic variation inhibits expression of its neighbouring SMG6 gene and protects against temporal lobe epilepsy. Journal of cellular and molecular medicine 5 29363864
2006 Crystallization and preliminary X-ray analysis of the PIN domain of human EST1A. Acta crystallographica. Section F, Structural biology and crystallization communications 5 16820686
2026 The PIN domain of SMG-5 functionally interacts with SMG-6 to stimulate NMD. RNA (New York, N.Y.) 3 41638882
2026 Active Site Assembly by SMG5 as a Mechanism for SMG6 Endonuclease Licencing in Nonsense-mediated mRNA Decay. Journal of molecular biology 3 41763597
2026 Composite SMG5-SMG6 PIN domain formation is essential for NMD. Nature communications 2 41714610
2026 SMG6's PIN (PilT N-Terminus) Domain Is Required for Nonsense-Mediated mRNA Decay (NMD) In Vivo. Cells 0 41677645

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