SMG6: Difference between revisions

'''Telomerase-binding protein EST1A''' is an [[enzyme]] that in humans is encoded by the ''SMG6'' [[gene]] on [[Chromosome 17 (human)|chromosome 17]].<ref name="pmid12676087">{{cite journal | vauthors = Reichenbach P, HossHöss M, Azzalin CM, Nabholz M, Bucher P, Lingner J | title = A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed | journal = CurrCurrent BiolBiology | volume = 13 | issue = 7 | pages = 568–74 | date =Apr April 2003 | pmid = 12676087 | pmc = | doi = 10.1016/S0960-9822(03)00173-8 }}</ref><ref name="pmid12699629">{{cite journal | vauthors = Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L | title = Functional conservation of the telomerase protein Est1p in humans | journal = CurrCurrent BiolBiology | volume = 13 | issue = 8 | pages = 698–704 | date =Apr April 2003 | pmid = 12699629 | pmc = | doi = 10.1016/S0960-9822(03)00210-0 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SMG6 Smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23293| accessdate = }}</ref> It is ubiquitously expressed in many tissues and cell types.<ref>{{Cite web|url=http://biogps.org/#goto=genereport&id=23293|title=BioGPS - your Gene Portal System|website=biogps.org|access-date=2016-10-12}}</ref> The C-terminus of the EST1A protein contains a [[PIN domain|PilT N-terminus (PIN) domain]]. This structure for this domain has been determined by [[X-ray crystallography]].<ref>{{cite journal |year vauthors =2006 Takeshita D, Zenno S, Lee WC, Saigo K, Tanokura M | title = Crystallization and preliminary X-ray analysis of the PIN domain of human EST1A. | journal = Acta CrystallogrCrystallographica. Sect.Section F, Struct.Structural Biol.Biology Cryst.and Crystallization Communications Commun.| volume = 62 | issue = Pt 7 | pages = 656–8 |doi date =10.1107/S1744309106020057|pmc=2242961 July 2006 | pmid = 16820686 |vauthors pmc =Takeshita D,2242961 Zenno| S,doi Lee= WC,10.1107/S1744309106020057 etal}}</ref> SMG6 functions to bind [[single-stranded DNA]] in [[telomere]] maintenance and [[Single-stranded DNA|single-stranded RNA]] in [[nonsense-mediated mRNA decay]] (NMD).<ref>{{Citecite journal |last vauthors = Snow|first=Bryan E.|last2=BE, Erdmann|first2=Natalie|last3= N, Cruickshank|first3=Jennifer|last4= J, Goldman|first4=Hartt|last5= H, Gill|first5=R. Montgomery|last6=RM, Robinson|first6=Murray O.|last7=MO, Harrington L |first7=Lea|date=2003-04-15| title = Functional conservation of the telomerase protein Est1p in humans |url=https://www.ncbi.nlm.nih.gov/pubmed/12699629| journal = Current biology:Biology CB| volume = 13 | issue = 8 | pages = 698–704 |issn date =0960-9822 April 2003 | pmid = 12699629 }}</ref><ref>{{Citecite journal |last vauthors = Huntzinger|first=Eric|last2= E, Kashima|first2=Isao|last3= I, Fauser|first3=Maria|last4= M, Saulière|first4=Jérôme|last5= J, Izaurralde E |first5=Elisa|date=2008-12-01| title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan |url=https://www.ncbi.nlm.nih.gov/pubmed/18974281| journal =RNA (NewRna York, N.Y.)| volume = 14 | issue = 12 | pages =2609–2617 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208|issn=1469-9001|pmid=18974281 }}</ref> The ''SMG6'' gene also contains one of 27 [[SNPs]] associated with increased risk of [[coronary artery disease]].<ref name=":0" />

SMG6 is one of three human [[homologs]] for Est1p found in [[Saccharomyces cerevisiae]]. It contains a PIN domain, which is characteristic of proteins with [[ribonuclease]] activity.<ref>{{Citecite journal |last vauthors = Glavan|first=Filip|last2= F, Behm-Ansmant|first2=Isabelle|last3= I, Izaurralde|first3=Elisa|last4= E, Conti E |first4=Elena|date=2006-11-01| title = Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex |url=https://www.ncbi.nlm.nih.gov/pubmed/17053788| journal = The EMBO journalJournal | volume = 25 | issue = 21 | pages =5117–5125 5117–25 | date = November 2006 | pmid = 17053788 | doi = 10.1038/sj.emboj.7601377|issn=0261-4189|pmid=17053788 }}</ref> The PIN domain forms an alpha/beta fold structure that similar to that found in 5' [[Nuclease|nucleases]].<ref>{{Citecite journal |last vauthors = Takeshita|first=Daijiro|last2= D, Zenno|first2=Shuhei|last3= S, Lee|first3=Woo Cheol|last4=WC, Saigo|first4=Kaoru|last5= K, Tanokura M |first5=Masaru|date=2007-09-01| title = Crystal structure of the PIN domain of human telomerase-associated protein EST1A |url=https://www.ncbi.nlm.nih.gov/pubmed/17557331| journal = Proteins | volume = 68 | issue = 4 | pages =980–989 980–9 | date = September 2007 | pmid = 17557331 | doi = 10.1002/prot.21351|issn=1097-0134|pmid=17557331 }}</ref> Within the PIN domain is a canonical triad of [[Amino acid|acidic residues]] that functions to cleave single-stranded RNA.<ref>{{Citecite journal |last vauthors = Huntzinger|first=Eric|last2= E, Kashima|first2=Isao|last3= I, Fauser|first3=Maria|last4= M, Saulière|first4=Jérôme|last5= J, Izaurralde E |first5=Elisa|date=2008-12-01| title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan |url=https://www.ncbi.nlm.nih.gov/pubmed/18974281| journal =RNA (New York,Rna N.Y.)| volume = 14 | issue = 12 | pages =2609–2617 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208|issn=1469-9001|pmid=18974281 }}</ref> SMG6 also shares a [[phosphoserine]]-binding domain resembling the one in [[14-3-3 protein|14–3–3 proteins]] with its other two homologs, [[SMG5]] and [[SMG7]]. This 14–3–3-like domain and a C-terminal helical hairpins domain with seven α-helices stacked perpendicular to the 14–3–3-like domain together form a monomeric tetratricopeptide region (TPR). Differences in the orientation and specific residues in the TPR between SMG6 and its homologs may account for why SMG6 does not form a [[Protein complexes|complex]] with SMG5 and SMG7 when recruited by [[UPF1]].<ref>{{Citecite journal |last vauthors = Chakrabarti|first=Sutapa|last2= S, Bonneau|first2=Fabien|last3= F, Schüssler|first3=Steffen|last4= S, Eppinger|first4=Elfriede|last5= E, Conti E |first5=Elena|date=2014-08-01| title = Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6 |url=https://www.ncbi.nlm.nih.gov/pubmed/25013172| journal = Nucleic Acids Research | volume = 42 | issue = 14 | pages =9447–9460 9447–60 | date = August 2014 | pmid = 25013172 | doi = 10.1093/nar/gku578|issn=1362-4962|pmid=25013172 }}</ref>

== Function ==

SMG6 is broadly expressed in all human tissues. It has dual functions in [[telomere]] maintenance and [[RNA]] surveillance pathways. SMG6 binds single-stranded telomere DNA and cooperates with [[telomerase]] reverse transcriptase to lengthen telomeres.<ref name="pmid12699629" /> Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response.<ref name="pmid10037601">{{cite journal |last1 vauthors = Karlseder|first1= J|last2=, Broccoli|first2= D|last3=, Dai|first3= Y|last4=, Hardy|first4= S|last5=, de Lange|first5= T | title = p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. | journal = Science (New| York,volume N.Y.)|date=26 February283 1999|volume=283| issue = 5406 | pages =1321-5 1321–5 | date = February 1999 | pmid = 10037601 }}</ref><ref name="pmid12676087" /> SMG6 also functions as an [[endonuclease]] in the [[NMD]] pathway. The catalytic activity of SMG6 resides in its [[PIN]] domain, which is required for the degradation of [[premature translation termination codons]] (PTC)-containing mRNAs in human cells. <ref name="pmid18974281">{{cite journal |last1 vauthors = Huntzinger|first1= E|last2=, Kashima|first2= I|last3=, Fauser|first3= M|last4=, Saulière|first4= J|last5=, Izaurralde|first5= E | title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. | journal =RNA (NewRna York, N.Y.)|date=December 2008|volume = 14 | issue = 12 | pages =2609-17 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 }}</ref> SMG6 cleaves mRNA near the premature translocation-termination codons and requires [[UPF1]] and [[SMG1]] to reduce reporter mRNA levels.<ref name="pmid25053839">{{cite journal |last1 vauthors = Nicholson|first1= P|last2=, Josi|first2= C|last3=, Kurosawa|first3= H|last4=, Yamashita|first4= A|last5=, Mühlemann|first5= O | title = A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD. | journal = Nucleic acidsAcids research|date=AugustResearch 2014| volume = 42 | issue = 14 | pages =9217-35 9217–35 | date = August 2014 | pmid = 25053839 | doi = 10.1093/nar/gku645 }}</ref>

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