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 | s2cid = 14423276 | doi-access = free }}</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 | s2cid = 6685276 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SMG6 Smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)| url = httphttps://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 Crystallogr.Crystallographica Sect.Section F Struct.| Biol. Cryst. 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 | doi=10.1016/s0960-9822(03)00210-0| s2cid = 6685276 | doi-access = free }}</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 (New York, N.Y.)| volume = 14 | issue = 12 | pages =2609–2617 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 |issn pmc=1469-9001|pmid=189742812590965}}</ref> The ''SMG6'' gene also contains one of 27 [[SNPs]] associated with increased risk of [[coronary artery disease]].<ref name=":0" />

The ''SMG6'' gene resides on chromosome 17 at the band 17p13.3 and contains 30 [[Exon|exons]].<ref>{{Cite web|url=httphttps://www.ncbi.nlm.nih.gov/gene/23293|title=SMG6 SMG6, nonsense mediated mRNA decay factor [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-10-12}}</ref> This gene produces 3 [[isoforms]] through [[alternative splicing]].<ref>{{Cite web|url=httphttps://www.uniprot.org/uniprot/Q86US8|title=SMG6 - Telomerase-binding protein EST1A - Homo sapiens (Human) - SMG6 gene & protein|website=www.uniprot.org|access-date=2016-10-12}}</ref>

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 pmc=0261-4189|pmid=170537881630413}}</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 s2cid =1097-0134|pmid=17557331 43477604 }}</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, N.Y.)| volume = 14 | issue = 12 | pages =2609–2617 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 |issn pmc=1469-9001|pmid=189742812590965}}</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 pmc=1362-4962|pmid=250131724132714}}</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">{{cite journal|last1=Snow|first1=BE|last2=Erdmann|first2=N|last3=Cruickshank|first3=J|last4=Goldman|first4=H|last5=Gill|first5=RM|last6=Robinson|first6=MO|last7=Harrington|first7=L|title=Functional conservation of the telomerase protein Est1p in humans.|journal=Current biology : CB|date=15 April 2003|volume=13|issue=8|pages=698-704|pmid=12699629}}</ref> 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|last1author1-link=Jan Karlseder |first1 vauthors = Karlseder 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|pmid=10037601}}</ref> <ref1321–5 name="pmid12676087">{{cite journal|last1=Reichenbach|first1=P|last2=Höss|first2=M|last3=Azzalin|first3=CM|last4=Nabholz|first4=M|last5=Bucher|first5=P|last6=Lingner|first6=J|title=A humandate homolog= ofFebruary yeast1999 Est1| associatespmid with telomerase and uncaps chromosome ends when overexpressed.|journal=Current biology10037601 : CB|date=1 April 2003|volumedoi=13|issue=7|pages=568-74|pmid=1267608710.1126/science.283.5406.1321}}</ref><ref name="pmid12676087" /> SMG6 also functions as an [[endonuclease]] in the [[Nonsense mediated decay|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 (New| York,volume N.Y.)|date=December 2008|volume=14 | issue = 12 | pages =2609-17 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 | pmc=2590965}}</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 | pmc=4132754}}</ref>

In humans, selected genomic regions based on 150 SNPs were identified in a [[genome-wide association study]] (GWAS) on coronary artery disease. Accordingly, the association between recent smoking and the CpG sites within and near these coronary artery disease-related genes were investigated in 724 [[Caucasian race|Caucasian]] subjects from the Rotterdam Study. The identified [[methylation]] sites were found in SMG6 together with other genes, and several of these sites exhibited lower methylation in subjects currently smoking compared to never smoking.<ref>{{cite journal | vauthors = Steenaard RV, Ligthart S, Stolk L, Peters MJ, van Meurs JB, Uitterlinden AG, Hofman A, Franco OH, Dehghan A | title = Tobacco smoking is associated with methylation of genes related to coronary artery disease | journal = Clinical Epigenetics | volume = 7 | pages = 54 | date = 2015-01-01 | issue = 1 | pmid = 26015811 | doi = 10.1186/s13148-015-0088-y | pmc=4443552 | doi-access = free }}</ref>

A multi-locus genetic risk score study based on a combination of 27 loci, including the SMG6 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).<ref name=":0">{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–71 | date = June 2015 | pmid = 25748612 | doi = 10.1016/S0140-6736(14)61730-X | pmc=4608367}}</ref>

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