SMG6

SMG6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2DOK, 2HWW, 2HWX, 4UM2
Identifiers
Aliases	SMG6, C17orf31, EST1A, SMG-6, hSMG5/7a, nonsense mediated mRNA decay factor, SMG6 nonsense mediated mRNA decay factor, hEST1A
External IDs	OMIM: 610963; MGI: 2144117; HomoloGene: 23024; GeneCards: SMG6; OMA:SMG6 - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17p13.3 Start 2,059,839 bp[1] End 2,303,785 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B5 Start 74,816,649 bp[2] End 75,055,274 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium anterior pituitary ganglionic eminence right adrenal gland canal of the cervix left adrenal gland right coronary artery sural nerve left uterine tube gastric mucosa Top expressed in spermatid ascending aorta aortic valve spermatocyte supraoptic nucleus secondary oocyte cumulus cell pituitary gland thymus lip More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding telomeric DNA binding metal ion binding DNA polymerase binding protein binding nuclease activity endonuclease activity hydrolase activity telomerase RNA binding endoribonuclease activity RNA binding ribonucleoprotein complex binding ribonuclease activity Cellular component cytoplasm cytosol exon-exon junction complex chromosome telomere telomerase catalytic core complex nucleolus telomerase holoenzyme complex nucleus Biological process nucleic acid phosphodiester bond hydrolysis mRNA export from nucleus negative regulation of telomere capping regulation of dephosphorylation nuclear-transcribed mRNA catabolic process, nonsense-mediated decay RNA phosphodiester bond hydrolysis, endonucleolytic regulation of RNA stability regulation of telomere maintenance regulation of telomere maintenance via telomerase regulation of telomerase activity telomere maintenance via telomerase RNA phosphodiester bond hydrolysis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23293 103677 Ensembl ENSG00000070366 ENSMUSG00000038290 UniProt Q86US8 P61406 RefSeq (mRNA) NM_001170957 NM_001256827 NM_001256828 NM_001282326 NM_017575 NM_001002764 RefSeq (protein) NP_001243756 NP_001243757 NP_001269255 NP_060045 NP_001002764 Location (UCSC) Chr 17: 2.06 – 2.3 Mb Chr 11: 74.82 – 75.06 Mb PubMed search [3] [4]
Wikidata
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Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17.^[5][6][7] It is ubiquitously expressed in many tissues and cell types.^[8] 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.^[9] SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD).^[10][11] The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.^[12]

Structure

Gene

The SMG6 gene resides on chromosome 17 at the band 17p13.3 and contains 30 exons.^[13] This gene produces 3 isoforms through alternative splicing.^[14]

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.^[15] The PIN domain forms an alpha/beta fold structure that similar to that found in 5' nucleases.^[16] Within the PIN domain is a canonical triad of acidic residues that functions to cleave single-stranded RNA.^[17] 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.^[18]

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.^[6] Overexpression of SMG6 induces anaphase bridges due to chromosome-end fusions and, thus, affects telomere capping, which may directly induce an apoptotic response.^[19][5] 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.^[20] SMG6 cleaves mRNA near the premature translocation-termination codons and requires UPF1 and SMG1 to reduce reporter mRNA levels.^[21]

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.^[22]

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).^[12]

References

Further reading