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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''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, Höss 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 = Current Biology | volume = 13 | issue = 7 | pages = 568–74 | date = 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 = Current Biology | volume = 13 | issue = 8 | pages = 698–704 | date = 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 = https://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 | vauthors = 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 Crystallographica Section F | volume = 62 | issue = Pt 7 | pages = 656–8 | date = July 2006 | pmid = 16820686 | pmc = 2242961 | doi = 10.1107/S1744309106020057 }}</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>{{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 = Current Biology | volume = 13 | issue = 8 | pages = 698–704 | date = April 2003 | pmid = 12699629 | doi=10.1016/s0960-9822(03)00210-0}}</ref><ref>{{cite journal | vauthors = Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E | title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan | journal = RNA | volume = 14 | issue = 12 | pages = 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 | pmc=2590965}}</ref> The ''SMG6'' gene also contains one of 27 [[SNPs]] associated with increased risk of [[coronary artery disease]].<ref name=":0" />
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image = PBB_Protein_SMG6_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2dok.
| PDB = {{PDB2|2dok}}, {{PDB2|2hww}}, {{PDB2|2hwx}}
| Name = Smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)
| HGNCid = 17809
| Symbol = SMG6
| AltSymbols =; C17orf31; EST1A; KIAA0732; SMG-6
| OMIM = 
| ECnumber = 
| Homologene = 23024
| MGIid = 2144117
| GeneAtlas_image1 = PBB_GE_SMG6_214940_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0042162 |text = telomeric DNA binding}}
| Component = {{GNF_GO|id=GO:0000781 |text = chromosome, telomeric region}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005694 |text = chromosome}} {{GNF_GO|id=GO:0005697 |text = telomerase holoenzyme complex}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0000184 |text = mRNA catabolic process, nonsense-mediated decay}} {{GNF_GO|id=GO:0000723 |text = telomere maintenance}} {{GNF_GO|id=GO:0006406 |text = mRNA export from nucleus}} {{GNF_GO|id=GO:0035303 |text = regulation of dephosphorylation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 23293
    | Hs_Ensembl = ENSG00000070366
    | Hs_RefseqProtein = NP_060045
    | Hs_RefseqmRNA = NM_017575
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 1909888
    | Hs_GenLoc_end = 2220160
    | Hs_Uniprot = Q86US8
    | Mm_EntrezGene = 103677
    | Mm_Ensembl = ENSMUSG00000038290
    | Mm_RefseqmRNA = NM_001002764
    | Mm_RefseqProtein = NP_001002764
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 74742056
    | Mm_GenLoc_end = 74980635
    | Mm_Uniprot = A0PJ64
  }}
}}
'''Smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)''', also known as '''SMG6''', is a human [[gene]].<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>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
=== Gene ===
{{PBB_Summary
The ''SMG6'' gene resides on chromosome 17 at the band 17p13.3 and contains 30 [[Exon|exons]].<ref>{{Cite web|url=https://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=https://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>
| section_title =  
| summary_text =  
}}


==References==
=== Protein ===
{{reflist|2}}
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>{{cite journal | vauthors = Glavan F, Behm-Ansmant I, Izaurralde E, Conti E | title = Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex | journal = The EMBO Journal | volume = 25 | issue = 21 | pages = 5117–25 | date = November 2006 | pmid = 17053788 | doi = 10.1038/sj.emboj.7601377 | pmc=1630413}}</ref> The PIN domain forms an alpha/beta fold structure that similar to that found in 5' [[Nuclease|nucleases]].<ref>{{cite journal | vauthors = Takeshita D, Zenno S, Lee WC, Saigo K, Tanokura M | title = Crystal structure of the PIN domain of human telomerase-associated protein EST1A | journal = Proteins | volume = 68 | issue = 4 | pages = 980–9 | date = September 2007 | pmid = 17557331 | doi = 10.1002/prot.21351 }}</ref> Within the PIN domain is a canonical triad of [[Amino acid|acidic residues]] that functions to cleave single-stranded RNA.<ref>{{cite journal | vauthors = Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E | title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan | journal = RNA | volume = 14 | issue = 12 | pages = 2609–17 | date = December 2008 | pmid = 18974281 | doi = 10.1261/rna.1386208 | pmc=2590965}}</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>{{cite journal | vauthors = Chakrabarti S, Bonneau F, Schüssler S, Eppinger E, Conti E | title = Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6 | journal = Nucleic Acids Research | volume = 42 | issue = 14 | pages = 9447–60 | date = August 2014 | pmid = 25013172 | doi = 10.1093/nar/gku578 | pmc=4132714}}</ref>
==Further reading==
 
{{refbegin | 2}}
== Function ==
{{PBB_Further_reading
 
| citations =
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 | vauthors = Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T | title = p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2 | journal = Science | volume = 283 | issue = 5406 | pages = 1321–5 | date = February 1999 | pmid = 10037601 | doi=10.1126/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 | vauthors = Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E | title = SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan | journal = RNA | volume = 14 | issue = 12 | pages = 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 | vauthors = Nicholson P, Josi C, Kurosawa H, Yamashita A, Mühlemann O | title = A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD | journal = Nucleic Acids Research | volume = 42 | issue = 14 | pages = 9217–35 | date = August 2014 | pmid = 25053839 | doi = 10.1093/nar/gku645 | pmc=4132754}}</ref>
*{{cite journal | author=Nakajima D, Okazaki N, Yamakawa H, ''et al.'' |title=Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. |journal=DNA Res. |volume=9 |issue= 3 |pages= 99-106 |year= 2003 |pmid= 12168954 |doi= }}
 
*{{cite journal | author=Nagase T, Ishikawa K, Suyama M, ''et al.'' |title=Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. |journal=DNA Res. |volume=5 |issue= 5 |pages= 277-86 |year= 1999 |pmid= 9872452 |doi= }}
== Clinical significance ==
*{{cite journal | author=Hoff C, Seranski P, Mollenhauer J, ''et al.'' |title=Physical and transcriptional mapping of the 17p13.3 region that is frequently deleted in human cancer. |journal=Genomics |volume=70 |issue= 1 |pages= 26-33 |year= 2001 |pmid= 11087658 |doi= 10.1006/geno.2000.6353 }}
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 | pmid = 26015811 | doi = 10.1186/s13148-015-0088-y | pmc=4443552}}</ref>
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal | author=Chiu SY, Serin G, Ohara O, Maquat LE |title=Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1. |journal=RNA |volume=9 |issue= 1 |pages= 77-87 |year= 2003 |pmid= 12554878 |doi= }}
=== Clinical marker ===
*{{cite journal | author=Reichenbach P, Höss M, Azzalin CM, ''et al.'' |title=A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed. |journal=Curr. Biol. |volume=13 |issue= 7 |pages= 568-74 |year= 2003 |pmid= 12676087 |doi= }}
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>
*{{cite journal | author=Snow BE, Erdmann N, Cruickshank J, ''et al.'' |title=Functional conservation of the telomerase protein Est1p in humans. |journal=Curr. Biol. |volume=13 |issue= 8 |pages= 698-704 |year= 2004 |pmid= 12699629 |doi= }}
{{clear}}
*{{cite journal | author=Ohnishi T, Yamashita A, Kashima I, ''et al.'' |title=Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. |journal=Mol. Cell |volume=12 |issue= 5 |pages= 1187-200 |year= 2004 |pmid= 14636577 |doi= }}
== References ==
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
{{reflist|33em}}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
 
*{{cite journal | author=Fukuhara N, Ebert J, Unterholzner L, ''et al.'' |title=SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. |journal=Mol. Cell |volume=17 |issue= 4 |pages= 537-47 |year= 2005 |pmid= 15721257 |doi= 10.1016/j.molcel.2005.01.010 }}
== Further reading ==
*{{cite journal | author=Azzalin CM, Lingner J |title=The human RNA surveillance factor UPF1 is required for S phase progression and genome stability. |journal=Curr. Biol. |volume=16 |issue= 4 |pages= 433-9 |year= 2006 |pmid= 16488880 |doi= 10.1016/j.cub.2006.01.018 }}
{{refbegin|33em}}
*{{cite journal | author=Takeshita D, Zenno S, Lee WC, ''et al.'' |title=Crystallization and preliminary X-ray analysis of the PIN domain of human EST1A. |journal=Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. |volume=62 |issue= Pt 7 |pages= 656-8 |year= 2006 |pmid= 16820686 |doi= 10.1107/S1744309106020057 }}
* {{cite journal | vauthors = Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T | title = Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones | journal = DNA Research | volume = 9 | issue = 3 | pages = 99–106 | date = June 2002 | pmid = 12168954 | doi = 10.1093/dnares/9.3.99 }}
*{{cite journal | author=Glavan F, Behm-Ansmant I, Izaurralde E, Conti E |title=Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex. |journal=EMBO J. |volume=25 |issue= 21 |pages= 5117-25 |year= 2007 |pmid= 17053788 |doi= 10.1038/sj.emboj.7601377 }}
* {{cite journal | vauthors = Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 5 | issue = 5 | pages = 277–86 | date = October 1998 | pmid = 9872452 | doi = 10.1093/dnares/5.5.277 }}
*{{cite journal | author=Takeshita D, Zenno S, Lee WC, ''et al.'' |title=Crystal structure of the PIN domain of human telomerase-associated protein EST1A. |journal=Proteins |volume=68 |issue= 4 |pages= 980-9 |year= 2007 |pmid= 17557331 |doi= 10.1002/prot.21351 }}
* {{cite journal | vauthors = Hoff C, Seranski P, Mollenhauer J, Korn B, Detzel T, Reinhardt R, Ramser J, Poustka A | title = Physical and transcriptional mapping of the 17p13.3 region that is frequently deleted in human cancer | journal = Genomics | volume = 70 | issue = 1 | pages = 26–33 | date = November 2000 | pmid = 11087658 | doi = 10.1006/geno.2000.6353 }}
}}
* {{cite journal | vauthors = Chiu SY, Serin G, Ohara O, Maquat LE | title = Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1 | journal = RNA | volume = 9 | issue = 1 | pages = 77–87 | date = January 2003 | pmid = 12554878 | pmc = 1370372 | doi = 10.1261/rna.2137903 }}
* {{cite journal | vauthors = Ohnishi T, Yamashita A, Kashima I, Schell T, Anders KR, Grimson A, Hachiya T, Hentze MW, Anderson P, Ohno S | title = Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7 | journal = Molecular Cell | volume = 12 | issue = 5 | pages = 1187–200 | date = November 2003 | pmid = 14636577 | doi = 10.1016/S1097-2765(03)00443-X }}
* {{cite journal | vauthors = Fukuhara N, Ebert J, Unterholzner L, Lindner D, Izaurralde E, Conti E | title = SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway | journal = Molecular Cell | volume = 17 | issue = 4 | pages = 537–47 | date = February 2005 | pmid = 15721257 | doi = 10.1016/j.molcel.2005.01.010 }}
* {{cite journal | vauthors = Azzalin CM, Lingner J | title = The human RNA surveillance factor UPF1 is required for S phase progression and genome stability | journal = Current Biology | volume = 16 | issue = 4 | pages = 433–9 | date = February 2006 | pmid = 16488880 | doi = 10.1016/j.cub.2006.01.018 }}
* {{cite journal | vauthors = 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 Crystallographica Section F | volume = 62 | issue = Pt 7 | pages = 656–8 | date = July 2006 | pmid = 16820686 | pmc = 2242961 | doi = 10.1107/S1744309106020057 }}
* {{cite journal | vauthors = Glavan F, Behm-Ansmant I, Izaurralde E, Conti E | title = Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex | journal = The EMBO Journal | volume = 25 | issue = 21 | pages = 5117–25 | date = November 2006 | pmid = 17053788 | pmc = 1630413 | doi = 10.1038/sj.emboj.7601377 }}
* {{cite journal | vauthors = Takeshita D, Zenno S, Lee WC, Saigo K, Tanokura M | title = Crystal structure of the PIN domain of human telomerase-associated protein EST1A | journal = Proteins | volume = 68 | issue = 4 | pages = 980–9 | date = September 2007 | pmid = 17557331 | doi = 10.1002/prot.21351 }}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=23293}}
{{WikiDoc Sources}}

Latest revision as of 06:50, 23 March 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] The C-terminus of the EST1A protein contains a PilT N-terminus (PIN) domain. This structure for this domain has been determined by X-ray crystallography.[5] SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD).[6][7] The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[8]

Structure

Gene

The SMG6 gene resides on chromosome 17 at the band 17p13.3 and contains 30 exons.[9] This gene produces 3 isoforms through alternative splicing.[10]

Protein

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.[11] The PIN domain forms an alpha/beta fold structure that similar to that found in 5' nucleases.[12] Within the PIN domain is a canonical triad of acidic residues that functions to cleave single-stranded RNA.[13] SMG6 also shares a phosphoserine-binding domain resembling the one in 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 complex with SMG5 and SMG7 when recruited by UPF1.[14]

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.[2] Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response.[15][1] 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.[16] SMG6 cleaves mRNA near the premature translocation-termination codons and requires UPF1 and SMG1 to reduce reporter mRNA levels.[17]

Clinical significance

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 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.[18]

Clinical marker

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).[8]

References

  1. ↑ Jump up to: 1.0 1.1 Reichenbach P, Höss M, Azzalin CM, Nabholz M, Bucher P, Lingner J (April 2003). "A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed". Current Biology. 13 (7): 568–74. doi:10.1016/S0960-9822(03)00173-8. PMID 12676087.
  2. ↑ Jump up to: 2.0 2.1 Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L (April 2003). "Functional conservation of the telomerase protein Est1p in humans". Current Biology. 13 (8): 698–704. doi:10.1016/S0960-9822(03)00210-0. PMID 12699629.
  3. ↑ "Entrez Gene: SMG6 Smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans)".
  4. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-12.
  5. ↑ Takeshita D, Zenno S, Lee WC, Saigo K, Tanokura M (July 2006). "Crystallization and preliminary X-ray analysis of the PIN domain of human EST1A". Acta Crystallographica Section F. 62 (Pt 7): 656–8. doi:10.1107/S1744309106020057. PMC 2242961. PMID 16820686.
  6. ↑ Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L (April 2003). "Functional conservation of the telomerase protein Est1p in humans". Current Biology. 13 (8): 698–704. doi:10.1016/s0960-9822(03)00210-0. PMID 12699629.
  7. ↑ Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E (December 2008). "SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan". RNA. 14 (12): 2609–17. doi:10.1261/rna.1386208. PMC 2590965. PMID 18974281.
  8. ↑ Jump up to: 8.0 8.1 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 (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
  9. ↑ "SMG6 SMG6, nonsense mediated mRNA decay factor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-12.
  10. ↑ "SMG6 - Telomerase-binding protein EST1A - Homo sapiens (Human) - SMG6 gene & protein". www.uniprot.org. Retrieved 2016-10-12.
  11. ↑ Glavan F, Behm-Ansmant I, Izaurralde E, Conti E (November 2006). "Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex". The EMBO Journal. 25 (21): 5117–25. doi:10.1038/sj.emboj.7601377. PMC 1630413. PMID 17053788.
  12. ↑ Takeshita D, Zenno S, Lee WC, Saigo K, Tanokura M (September 2007). "Crystal structure of the PIN domain of human telomerase-associated protein EST1A". Proteins. 68 (4): 980–9. doi:10.1002/prot.21351. PMID 17557331.
  13. ↑ Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E (December 2008). "SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan". RNA. 14 (12): 2609–17. doi:10.1261/rna.1386208. PMC 2590965. PMID 18974281.
  14. ↑ Chakrabarti S, Bonneau F, Schüssler S, Eppinger E, Conti E (August 2014). "Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6". Nucleic Acids Research. 42 (14): 9447–60. doi:10.1093/nar/gku578. PMC 4132714. PMID 25013172.
  15. ↑ Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T (February 1999). "p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2". Science. 283 (5406): 1321–5. doi:10.1126/science.283.5406.1321. PMID 10037601.
  16. ↑ Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E (December 2008). "SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan". RNA. 14 (12): 2609–17. doi:10.1261/rna.1386208. PMC 2590965. PMID 18974281.
  17. ↑ Nicholson P, Josi C, Kurosawa H, Yamashita A, Mühlemann O (August 2014). "A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD". Nucleic Acids Research. 42 (14): 9217–35. doi:10.1093/nar/gku645. PMC 4132754. PMID 25053839.
  18. ↑ Steenaard RV, Ligthart S, Stolk L, Peters MJ, van Meurs JB, Uitterlinden AG, Hofman A, Franco OH, Dehghan A (2015-01-01). "Tobacco smoking is associated with methylation of genes related to coronary artery disease". Clinical Epigenetics. 7: 54. doi:10.1186/s13148-015-0088-y. PMC 4443552. PMID 26015811.

Further reading

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