{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMG6 is a multifunctional factor that harbors a conserved endonuclease domain of the PIN‐fold family. Structural studies of the yeast Est1p homolog, human EST1A (also known as SMG6), reveal a PIN domain with an active center resembling that of 5′ nucleases, suggesting that its catalytic activity underlies a key mechanism for RNA cleavage. This domain also supports interactions with telomerase components, as SMG6 can bind to telomerase RNA (hTR) and form RNA‐independent contacts with the telomerase reverse transcriptase to modulate telomere homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the context of messenger RNA quality control, SMG6 plays an essential role in nonsense-mediated mRNA decay (NMD). It is recruited to aberrant transcripts through direct interactions with the exon junction complex (EJC) via conserved EJC-binding motifs and by engaging phosphorylated UPF1 through distinct, phosphorylation-independent contacts. These unique modes of interaction differentiate SMG6 from other NMD effectors such as SMG5 and SMG7, underscoring its specific function as the endonuclease that initiates decay of mRNAs harboring premature termination codons."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent transcriptome-wide mapping studies have delineated a preferred sequence motif at SMG6 cleavage sites, establishing that for many NMD substrates—particularly those containing premature termination codons—SMG6-mediated endocleavage is a constitutive and decisive degradative event. Moreover, transcripts with features such as upstream open reading frames or long 3′ UTRs may be alternatively degraded through additional exonucleolytic decay routes involving SMG7, although SMG6 and SMG7 often target essentially overlapping sets of mRNAs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, the efficiency of SMG6-mediated endonucleolytic cleavage is modulated by translation termination dynamics. Factors that affect ribosome stalling or promote readthrough at termination codons can diminish the recruitment and/or activity of SMG6 on its target mRNAs, highlighting a critical link between translation termination fidelity and the activation of mRNA decay pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daijiro Takeshita, Shuhei Zenno, Woo Cheol Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of the PIN domain of human telomerase-associated protein EST1A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proteins (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/prot.21351"}], "href": "https://doi.org/10.1002/prot.21351"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17557331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17557331"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sophie Redon, Patrick Reichenbach, Joachim Lingner "}, {"type": "b", "children": [{"type": "t", "text": "Protein RNA and protein protein interactions mediate association of human EST1A/SMG6 with telomerase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkm724"}], "href": "https://doi.org/10.1093/nar/gkm724"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17940095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17940095"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Isao Kashima, Stefanie Jonas, Uma Jayachandran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.604610"}], "href": "https://doi.org/10.1101/gad.604610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20930030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20930030"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sutapa Chakrabarti, Fabien Bonneau, Steffen Schüssler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gku578"}], "href": "https://doi.org/10.1093/nar/gku578"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25013172"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25013172"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Pamela Nicholson, Christoph Josi, Hitomi Kurosawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gku645"}], "href": "https://doi.org/10.1093/nar/gku645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25053839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25053839"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Skye A Schmidt, Patricia L Foley, Dong-Hoon Jeong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of SMG6 cleavage sites and a preferred RNA cleavage motif by global analysis of endogenous NMD targets in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gku1258"}], "href": "https://doi.org/10.1093/nar/gku1258"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25429978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25429978"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Martino Colombo, Evangelos D Karousis, Joël Bourquin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.059055.116"}], "href": "https://doi.org/10.1261/rna.059055.116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27864472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27864472"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Franziska Ottens, Volker Boehm, Christopher R Sibley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcript-specific characteristics determine the contribution of endo- and exonucleolytic decay pathways during the degradation of nonsense-mediated decay substrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.059659.116"}], "href": "https://doi.org/10.1261/rna.059659.116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28461625"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28461625"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Giuditta Annibaldis, Michal Domanski, René Dreos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Readthrough of stop codons under limiting ABCE1 concentration involves frameshifting and inhibits nonsense-mediated mRNA decay."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkaa758"}], "href": "https://doi.org/10.1093/nar/gkaa758"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32941650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32941650"}]}]}]}