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==Overview==
==Overview==


The [[Translation (biology)|translation]] of [[messenger RNA]] transcripts into proteins is a vital part of the [[central dogma of molecular biology]]. mRNA molecules are, however, prone to a host of fidelity errors which can cause errors in translation of mRNA into quality [[proteins]].<ref name="Amrani">Amrani, N., Sachs, M.S. and Jacobson, A. (2006) Early nonsense:mRNA decay solves a translational problem. Nat. Mol. Cell.Biol. 7, 415–425.</ref> RNA surveillance mechanisms are methods cells use to assure the quality and fidelity of the mRNA molecules.<ref>{{cite journal | last1 = Moore | first1 = M.J. | year = 2005 | title = From birth to death: the complex lives of eukaryotic mRNAs | url = | journal = Science | volume = 309 | issue = | pages = 1514–1518 | doi=10.1126/science.1111443}}</ref> This is generally achieved through marking aberrant mRNA molecule for [[Chemical decomposition|degradation]] by various endogenous [[nuclease]]s.<ref name="Amrani2">Amrani, R. Ganesan, S. Kervestin, D.A. Mangus, S. Ghosh and A. Jacobson, A faux 3′-[[Untranslated Region|UTR]] promotes aberrant termination and triggers nonsense-mediated mRNA decay, Nature 432 (2004), pp. 112–118.</ref>
The [[Translation (biology)|translation]] of [[messenger RNA]] transcripts into proteins is a vital part of the [[central dogma of molecular biology]]. mRNA molecules are, however, prone to a host of fidelity errors which can cause errors in translation of mRNA into quality [[proteins]].<ref name="Amrani">Amrani, N., Sachs, M.S. and Jacobson, A. (2006) Early nonsense:mRNA decay solves a translational problem. Nat. Mol. Cell.Biol. 7, 415–425.</ref> RNA surveillance mechanisms are methods cells use to assure the quality and fidelity of the mRNA molecules.<ref>{{cite journal | vauthors = Moore MJ | title = From birth to death: the complex lives of eukaryotic mRNAs | journal = Science | volume = 309 | issue = 5740 | pages = 1514–8 | date = September 2005 | pmid = 16141059 | doi = 10.1126/science.1111443 }}</ref> This is generally achieved through marking aberrant mRNA molecule for [[Chemical decomposition|degradation]] by various endogenous [[nuclease]]s.<ref name="Amrani2">Amrani, R. Ganesan, S. Kervestin, D.A. Mangus, S. Ghosh and A. Jacobson, A faux 3′-[[Untranslated Region|UTR]] promotes aberrant termination and triggers nonsense-mediated mRNA decay, Nature 432 (2004), pp. 112–118.</ref>


mRNA surveillance has been documented in [[bacteria]] and [[yeast]]. In [[eukaryote]]s, these mechanisms are known to function in both the [[cell nucleus|nucleus]] and [[cytoplasm]].<ref name="Fasken">{{cite journal | last1 = Fasken | first1 = M.B. | last2 = Corbett | first2 = A.H. | year = 2005 | title = Process or perish: quality control in mRNA biogenesis | url = | journal = Nat. Struct. Mol. Biol. | volume = 12 | issue = | pages = 482–488 | doi=10.1038/nsmb945}}</ref> Fidelity checks of mRNA molecules in the nucleus results in the degradation of improperly processed transcripts before export into the cytoplasm. Transcripts are subject to further surveillance once in the cytoplasm. Cytoplasmic surveillance mechanisms assess mRNA [[Transcription (genetics)|transcripts]] for the absence of or presence of premature stop codons.<ref name="Amrani2" /><ref name="Fasken" />
mRNA surveillance has been documented in [[bacteria]] and [[yeast]]. In [[eukaryote]]s, these mechanisms are known to function in both the [[cell nucleus|nucleus]] and [[cytoplasm]].<ref name="Fasken">{{cite journal | vauthors = Fasken MB, Corbett AH | title = Process or perish: quality control in mRNA biogenesis | journal = Nature Structural & Molecular Biology | volume = 12 | issue = 6 | pages = 482–8 | date = June 2005 | pmid = 15933735 | doi = 10.1038/nsmb945 }}</ref> Fidelity checks of mRNA molecules in the nucleus results in the degradation of improperly processed transcripts before export into the cytoplasm. Transcripts are subject to further surveillance once in the cytoplasm. Cytoplasmic surveillance mechanisms assess mRNA [[Transcription (genetics)|transcripts]] for the absence of or presence of premature stop codons.<ref name="Amrani2" /><ref name="Fasken" />


Three surveillance mechanisms are currently known to function within [[Cell (biology)|cells]]: the nonsense-mediated mRNA decay pathway (NMD); the nonstop mediated mRNA decay pathways (NSD); and the no-go mediated mRNA decay pathway (NGD).
Three surveillance mechanisms are currently known to function within [[Cell (biology)|cells]]: the nonsense-mediated mRNA decay pathway (NMD); the nonstop mediated mRNA decay pathways (NSD); and the no-go mediated mRNA decay pathway (NGD).
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=== Overview ===
=== Overview ===


Nonsense-mediated decay is involved in detection and decay of mRNA transcripts which contain premature termination codons (PTCs). PTCs can arise in cells through various mechanisms: [[germline]] mutations in DNA; [[Somatic (biology)|somatic]] mutations in DNA; errors in [[Transcription (genetics)|transcription]]; or errors in post transcriptional mRNA processing.<ref name="jebus">Chang, Y.F., Imam, J.S. and Wilkinson, M.F. (2007) The nonsense-mediated decay RNA surveillance pathway. Biochem. 76, 51–74.</ref><ref name= "Rehwinkel">{{cite journal | last1 = Rehwinkel | first1 = J. | last2 = Raes | first2 = J. | last3 = Izaurralde | first3 = E. | year = 2006 | title = Nonsense-mediated mRNA decay: target genes and functional diversification of effectors | url = | journal = Trends Biochem Sci | volume = 31 | issue = | pages = 639–646 | doi=10.1016/j.tibs.2006.09.005}}</ref> Failure to recognize and decay these mRNA transcripts can result in the production of truncated proteins which may be harmful to the organism. By causing decay of C-terminally [[Mutation|truncated]] polypeptides, the NMD mechanism can protect cells against deleterious [[Dominance (genetics)|dominant]]-negative, and [[gain of function]] effects.<ref name="Maquat">{{cite journal | last1 = Maquat | first1 = L.E. | year = 2004 | title = Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat | url = | journal = Mol. Cell. Biol. | volume = 5 | issue = | pages = 89–99 | doi=10.1038/nrm1310}}</ref> PTCs have been implicated in approximately 30% of all [[heredity|inherited]] diseases; as such, the NMD pathway plays a vital role in assuring overall survival and fitness of an organism<ref>{{cite journal | last1 = Holbrook | first1 = J.A. | last2 = Neu-Yilik | first2 = G. | last3 = Hentze | first3 = A.E. | last4 = Kulozik | first4 = M.W. | year = 2004 | title = nonsensemediated decay approaches the clinic | url = | journal = Nat. Genet. | volume = 36 | issue = | pages = 801–808 | doi=10.1038/ng1403}}</ref><ref>{{cite journal | last1 = Mendell | first1 = J.T. | last2 = Sharifi | first2 = N.A. | last3 = Meyers | first3 = J.L. | last4 = Martinez-Murillo | first4 = F. | last5 = Dietz | first5 = H.C. | year = 2004 | title = Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise | url = | journal = Nat. Genet. | volume = 36 | issue = | pages = 1073–1078 | doi=10.1038/ng1429}}</ref>
Nonsense-mediated decay is involved in detection and decay of mRNA transcripts which contain premature termination codons (PTCs). PTCs can arise in cells through various mechanisms: [[germline]] mutations in DNA; [[Somatic (biology)|somatic]] mutations in DNA; errors in [[Transcription (genetics)|transcription]]; or errors in post transcriptional mRNA processing.<ref name="jebus">Chang, Y.F., Imam, J.S. and Wilkinson, M.F. (2007) The nonsense-mediated decay RNA surveillance pathway. Biochem. 76, 51–74.</ref><ref name= "Rehwinkel">{{cite journal | vauthors = Rehwinkel J, Raes J, Izaurralde E | title = Nonsense-mediated mRNA decay: Target genes and functional diversification of effectors | journal = Trends in Biochemical Sciences | volume = 31 | issue = 11 | pages = 639–46 | date = November 2006 | pmid = 17010613 | doi = 10.1016/j.tibs.2006.09.005 }}</ref> Failure to recognize and decay these mRNA transcripts can result in the production of truncated proteins which may be harmful to the organism. By causing decay of C-terminally [[Mutation|truncated]] polypeptides, the NMD mechanism can protect cells against deleterious [[Dominance (genetics)|dominant]]-negative, and [[gain of function]] effects.<ref name="Maquat">{{cite journal | vauthors = Maquat LE | title = Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics | journal = Nature Reviews. Molecular Cell Biology | volume = 5 | issue = 2 | pages = 89–99 | date = February 2004 | pmid = 15040442 | doi = 10.1038/nrm1310 }}</ref> PTCs have been implicated in approximately 30% of all [[heredity|inherited]] diseases; as such, the NMD pathway plays a vital role in assuring overall survival and fitness of an organism<ref>{{cite journal | vauthors = Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE | title = Nonsense-mediated decay approaches the clinic | journal = Nature Genetics | volume = 36 | issue = 8 | pages = 801–8 | date = August 2004 | pmid = 15284851 | doi = 10.1038/ng1403 }}</ref><ref>{{cite journal | vauthors = Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC | title = Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise | journal = Nature Genetics | volume = 36 | issue = 10 | pages = 1073–8 | date = October 2004 | pmid = 15448691 | doi = 10.1038/ng1429 }}</ref>


A surveillance complex consisting of various proteins (eRF1, eRF3, Upf1, Upf2 and Upf3) is assembled and scans the mRNA for premature stop codons.<ref name="jebus" /> The assembly of this complex is triggered by premature translation termination. If a premature stop codon is detected then the mRNA transcript is signalled for degradation – the coupling of detection with degradation occurs.<ref name="Amrani2" /><ref name="Legeune">{{cite journal | last1 = Lejeune | first1 = F. | last2 = Maquat | first2 = L.E. | year = 2005 | title = Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells | url = | journal = Curr. Opin. Cell Biol. | volume = 17 | issue = | pages = 309–315 | doi=10.1016/j.ceb.2005.03.002}}</ref><ref name="Conti">{{cite journal | last1 = Conti | first1 = E. | last2 = Izaurralde | first2 = E. | year = 2005 | title = Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species | url = | journal = Curr. Opin. Cell Biol. | volume = 17 | issue = | pages = 316–325 | doi=10.1016/j.ceb.2005.04.005}}</ref>
A surveillance complex consisting of various proteins (eRF1, eRF3, Upf1, Upf2 and Upf3) is assembled and scans the mRNA for premature stop codons.<ref name="jebus" /> The assembly of this complex is triggered by premature translation termination. If a premature stop codon is detected then the mRNA transcript is signalled for degradation – the coupling of detection with degradation occurs.<ref name="Amrani2" /><ref name="Legeune">{{cite journal | vauthors = Lejeune F, Maquat LE | title = Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells | journal = Current Opinion in Cell Biology | volume = 17 | issue = 3 | pages = 309–15 | date = June 2005 | pmid = 15901502 | doi = 10.1016/j.ceb.2005.03.002 }}</ref><ref name="Conti">{{cite journal | vauthors = Conti E, Izaurralde E | title = Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species | journal = Current Opinion in Cell Biology | volume = 17 | issue = 3 | pages = 316–25 | date = June 2005 | pmid = 15901503 | doi = 10.1016/j.ceb.2005.04.005 }}</ref>


Seven smg genes (smg1-7) and three UPF genes (Upf1-3) have been identified in ''[[Saccharomyces cerevisiae]]'' and ''[[Caenorhabditis elegans]]'' as essential trans-acting factors contributing to NMD activity.<ref name="Cali">{{cite journal | last1 = Cali | first1 = B.M. | last2 = Kuchma | first2 = S.L. | last3 = Latham | first3 = J. | last4 = Anderson | first4 = P. | year = 1999 | title = smg-7 is required for mRNA surveillance in Caenorhabditis elegans | url = | journal = Genetics | volume = 151 | issue = | pages = 605–616 }}</ref><ref name="Yasha">{{cite journal | last1 = Yamashita | first1 = A. | last2 = Kashima | first2 = I. | last3 = Ohno | first3 = S. | year = 2005 | title = The role of SMG-1 in nonsense-mediated mRNA decay | url = | journal = Biochim. Biophys. Acta | volume = 1754 | issue = | pages = 305–315 | doi=10.1016/j.bbapap.2005.10.002}}</ref> All of these genes are [[Conserved sequence|conserved]] in ''[[Drosophila melanogaster]]'' and further mammals where they also play critical roles in NMD. Throughout eukaryotes there are three components which are conserved in the process of NMD.<ref name= "Kim">{{cite journal | last1 = Kim | first1 = Y.K. | last2 = Furic | first2 = L. | last3 = Desgroseillers | first3 = L. | last4 = Maquat | first4 = L.E. | year = 2005 | title = Mammalian Staufen1 recruits Upf1 to specific mRNA 3_UTRs so as to elicit mRNA decay | url = | journal = Cell | volume = 120 | issue = | pages = 195–208 | doi=10.1016/j.cell.2004.11.050}}</ref> These are the Upf1/SMG-2, Upf2/SMG-3 and Upf3/SMG-4 complexes. Upf1/SMG-2 is a phosphoprotein in multicellular organisms and is thought to contribute to NMD via its phosphorylation activity. However, the exact interactions of the proteins and their roles in NMD are currently disputed.<ref name="Conti" /><ref name="Cali" /><ref name="Kim" /><ref>Longman, D., Plasterk, R.H., Johnstone, I.L. and Caceres, J.F. (2007) Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. Genes Dev. 21, 1075–1085.</ref><ref name= "Gatfield">{{cite journal | last1 = Gatfield | first1 = D. | last2 = Unterholzner | first2 = L. | last3 = Ciccarelli | first3 = F.D. | last4 = Bork | first4 = P. | last5 = Izaurralde | first5 = E. | year = 2003 | title = Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways | url = | journal = EMBO J | volume = 22 | issue = | pages = 3960–3970 | doi=10.1093/emboj/cdg371| pmc = 169044 }}</ref>
Seven smg genes (smg1-7) and three UPF genes (Upf1-3) have been identified in ''[[Saccharomyces cerevisiae]]'' and ''[[Caenorhabditis elegans]]'' as essential trans-acting factors contributing to NMD activity.<ref name="Cali">{{cite journal | vauthors = Cali BM, Kuchma SL, Latham J, Anderson P | title = smg-7 is required for mRNA surveillance in Caenorhabditis elegans | journal = Genetics | volume = 151 | issue = 2 | pages = 605–16 | date = February 1999 | pmid = 9927455 }}</ref><ref name="Yasha">{{cite journal | vauthors = Yamashita A, Kashima I, Ohno S | title = The role of SMG-1 in nonsense-mediated mRNA decay | journal = Biochimica et Biophysica Acta | volume = 1754 | issue = 1-2 | pages = 305–15 | date = December 2005 | pmid = 16289965 | doi = 10.1016/j.bbapap.2005.10.002 }}</ref> All of these genes are [[Conserved sequence|conserved]] in ''[[Drosophila melanogaster]]'' and further mammals where they also play critical roles in NMD. Throughout eukaryotes there are three components which are conserved in the process of NMD.<ref name= "Kim">{{cite journal | vauthors = Kim YK, Furic L, Desgroseillers L, Maquat LE | title = Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay | journal = Cell | volume = 120 | issue = 2 | pages = 195–208 | date = January 2005 | pmid = 15680326 | doi = 10.1016/j.cell.2004.11.050 }}</ref> These are the Upf1/SMG-2, Upf2/SMG-3 and Upf3/SMG-4 complexes. Upf1/SMG-2 is a phosphoprotein in multicellular organisms and is thought to contribute to NMD via its phosphorylation activity. However, the exact interactions of the proteins and their roles in NMD are currently disputed.<ref name="Conti" /><ref name="Cali" /><ref name="Kim" /><ref>{{cite journal | vauthors = Longman D, Plasterk RH, Johnstone IL, Cáceres JF | title = Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway | journal = Genes & Development | volume = 21 | issue = 9 | pages = 1075–85 | date = May 2007 | pmid = 17437990 | doi = 10.1101/gad.417707 }}</ref><ref name= "Gatfield">{{cite journal | vauthors = Gatfield D, Unterholzner L, Ciccarelli FD, Bork P, Izaurralde E | title = Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways | journal = The EMBO Journal | volume = 22 | issue = 15 | pages = 3960–70 | date = August 2003 | pmid = 12881430 | pmc = 169044 | doi = 10.1093/emboj/cdg371 }}</ref>


===Mechanism in mammals===
===Mechanism in mammals===
[[Image:vertebratemechanism.jpg|thumb|400px|Nonsense mediated decay in mammals is mediated by the exon-exon junction. This junction is marked by a group of proteins which constitute the exon junction complex (EJC). The EJC recruits UPF1/SMG by transcription factors eRF1/eRF3. Interactions of these proteins lead to the assembly of the surveillance complex. This complex is ultimately responsible for the degradation of the nonsense mRNA.<ref name="jebus" />]]
[[Image:vertebratemechanism.jpg|thumb|400px|Nonsense mediated decay in mammals is mediated by the exon-exon junction. This junction is marked by a group of proteins which constitute the exon junction complex (EJC). The EJC recruits UPF1/SMG by transcription factors eRF1/eRF3. Interactions of these proteins lead to the assembly of the surveillance complex. This complex is ultimately responsible for the degradation of the nonsense mRNA.<ref name="jebus" />]]


A premature stop codon must be recognized as different from a normal stop codon so that only the former triggers a NMD response. It has been observed that the ability of a nonsense codon to cause mRNA degradation depends on its relative location to the downstream sequence element and associated proteins.<ref name="Amrani" /> Studies have demonstrated that [[nucleotides]] more than 50–54 nucleotides upstream of the last exon-exon junction can target mRNA for decay.<ref name="Amrani" /><ref name="Fasken" /><ref name="jebus" /><ref name="Rehwinkel" /><ref name="Maquat" /><ref name="Nagy">Nagy, E. and Maquat, L.E. (1998) A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. TrendBiochem. Sci. 23, 198–199. [13] Zhang, J., Sun, X., Qian, Y., L</ref> Those downstream from this region are unable to do so. Thus, nonsense codons lie more than 50-54 nucleotides upstream from the last [[exon]] boundary whereas natural stop codons are located within terminal exons.<ref name= "Zhang">{{cite journal | last1 = Zhang | first1 = J. | last2 = Sun | first2 = X. | last3 = Qian | first3 = Y. | last4 = LaDuca | first4 = J.P. | last5 = Maquat | first5 = L.E. | year = 1998 | title = At least one intron is required for the nonsense-mediated decay of triosephosphate isomerase mRNA: a possible link between nuclear splicing and cytoplasmic translation | url = | journal = Mol. Cell. Biol. | volume = 18 | issue = | pages = 5272–5283 | doi=10.1128/mcb.18.9.5272| pmc = 109113 }}</ref> [[Exon junction complex]]es (EJCs) mark the exon-exon boundaries. EJCs are multiprotein complexes that assemble during splicing at a position about 20–24 nucleotides upstream from the splice junction.<ref name="Neu-Yilik">{{cite journal | last1 = Neu-Yilik | first1 = G. | last2 = Gehring | first2 = N.H. | last3 = Thermann | first3 = R. | last4 = Frede | first4 = U. | last5 = Hentze | first5 = M.W. | last6 = Kulozik | first6 = A.E. | year = 2001 | title = Splicing and 30 end formation in the definition of nonsensemediated decay-competent human beta-globin mRNPs | url = | journal = EMBO J | volume = 20 | issue = | pages = 532–540 | doi=10.1093/emboj/20.3.532| pmc = 133467 }}</ref> It is this EJC that provides position information needed to discriminate premature stop codons from natural stop codons. Recognition of PTCs appears to be dependent on the definitions of the exon-exon junctions. This suggests involvement of the spliceosome in mammalian NMD.<ref name="Nagy" /><ref name="Behm">Behm-Ansmant, I., Gatfield, D., Rehwinkel, J., Hilgers.V., and Izaurralde, J., A conserved role for cytoplasmic poly(A)-binding protein 1 (PABPC1) in nonsense-mediated mRNA decay, EMBO J. 26 (2007), pp. 1591–1601.</ref> Research has investigated the possibility of spliceosome involvement in mammalian NMD and has determined this is a likely possibility.<ref name="Zhang" /> Furthermore, it has been observed that NMD mechanisms are not activated by nonsense transcripts that are generated from genes that naturally do not contain introns (i.e. Histone H4, Hsp70, melanocortin-4-receptor).<ref name="Maquat" />
A premature stop codon must be recognized as different from a normal stop codon so that only the former triggers a NMD response. It has been observed that the ability of a nonsense codon to cause mRNA degradation depends on its relative location to the downstream sequence element and associated proteins.<ref name="Amrani" /> Studies have demonstrated that [[nucleotides]] more than 50–54 nucleotides upstream of the last exon-exon junction can target mRNA for decay.<ref name="Amrani" /><ref name="Fasken" /><ref name="jebus" /><ref name="Rehwinkel" /><ref name="Maquat" /><ref name="Nagy">{{cite journal | vauthors = Nagy E, Maquat LE | title = A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance | journal = Trends in Biochemical Sciences | volume = 23 | issue = 6 | pages = 198–9 | date = June 1998 | pmid = 9644970 | doi = | url = }}</ref> Those downstream from this region are unable to do so. Thus, nonsense codons lie more than 50-54 nucleotides upstream from the last [[exon]] boundary whereas natural stop codons are located within terminal exons.<ref name= "Zhang">{{cite journal | vauthors = Player TJ, Mills DJ, Horton AA | title = Lipid peroxidation of the microsomal fraction and extracted microsomal lipids from DAB-induced hepatomas | journal = British Journal of Cancer | volume = 39 | issue = 6 | pages = 773–8 | date = June 1979 | pmc = 109113 | doi = 10.1128/mcb.18.9.5272 }}</ref> [[Exon junction complex]]es (EJCs) mark the exon-exon boundaries. EJCs are multiprotein complexes that assemble during splicing at a position about 20–24 nucleotides upstream from the splice junction.<ref name="Neu-Yilik">{{cite journal | vauthors = Neu-Yilik G, Gehring NH, Thermann R, Frede U, Hentze MW, Kulozik AE | title = Splicing and 3' end formation in the definition of nonsense-mediated decay-competent human beta-globin mRNPs | journal = The EMBO Journal | volume = 20 | issue = 3 | pages = 532–40 | date = February 2001 | pmid = 11157759 | pmc = 133467 | doi = 10.1093/emboj/20.3.532 }}</ref> It is this EJC that provides position information needed to discriminate premature stop codons from natural stop codons. Recognition of PTCs appears to be dependent on the definitions of the exon-exon junctions. This suggests involvement of the spliceosome in mammalian NMD.<ref name="Nagy" /><ref name="Behm">{{cite journal | vauthors = Behm-Ansmant I, Gatfield D, Rehwinkel J, Hilgers V, Izaurralde E | title = A conserved role for cytoplasmic poly(A)-binding protein 1 (PABPC1) in nonsense-mediated mRNA decay | journal = The EMBO Journal | volume = 26 | issue = 6 | pages = 1591–601 | date = March 2007 | pmid = 17318186 | pmc = 1829367 | doi = 10.1038/sj.emboj.7601588 }}</ref> Research has investigated the possibility of spliceosome involvement in mammalian NMD and has determined this is a likely possibility.<ref name="Zhang" /> Furthermore, it has been observed that NMD mechanisms are not activated by nonsense transcripts that are generated from genes that naturally do not contain introns (i.e. Histone H4, Hsp70, melanocortin-4-receptor).<ref name="Maquat" />


When the [[ribosome]] reaches a PTC the translation factors eRF1 and eRF3 interact with retained EJC complexes though a multiprotein bridge.<ref name="Kashima" /> The interactions of [[UPF1]] with the terminating complex and with [[UPF2]]/UPF3 of the retained EJCs are critical. It is these interactions which target the mRNA for rapid [[Decomposition|decay]] by endogenous nucleases<ref name="Zhang" /><ref name="Kashima">Kashima, I., Yamashita, A., Izumi, N., Kataoka, N., Morishita, R., Hoshino, S., Ohno, M., Dreyfuss, G., and Ohno, S. 2006. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsensemediated mRNA decay. Genes Dev. 20: 355–367.</ref>
When the [[ribosome]] reaches a PTC the translation factors eRF1 and eRF3 interact with retained EJC complexes though a multiprotein bridge.<ref name="Kashima" /> The interactions of [[UPF1]] with the terminating complex and with [[UPF2]]/UPF3 of the retained EJCs are critical. It is these interactions which target the mRNA for rapid [[Decomposition|decay]] by endogenous nucleases<ref name="Zhang" /><ref name="Kashima">{{cite journal | vauthors = Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S | title = Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay | journal = Genes & Development | volume = 20 | issue = 3 | pages = 355–67 | date = February 2006 | pmid = 16452507 | pmc = 1361706 | doi = 10.1101/gad.1389006 }}</ref>


[[Image:Wikiinvertmechanism.jpg|thumb|left|400px|Nonsense mediated mRNA decay in invertebrates is postulated to be mediated by the presence of a faux 3' untranslated region (UTR). These faux 3'UTRs are distinguished from natural 3'UTRs which follow natural stop codons. This is due to the lack of binding proteins which are normally present in natural 3'UTR. These binding proteins include the poly(A)-binding protein (PABP).<ref name="jebus" />]]
[[Image:Wikiinvertmechanism.jpg|thumb|left|400px|Nonsense mediated mRNA decay in invertebrates is postulated to be mediated by the presence of a faux 3' untranslated region (UTR). These faux 3'UTRs are distinguished from natural 3'UTRs which follow natural stop codons. This is due to the lack of binding proteins which are normally present in natural 3'UTR. These binding proteins include the poly(A)-binding protein (PABP).<ref name="jebus" />]]
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===Mechanism in invertebrates===
===Mechanism in invertebrates===


Studies involving organisms such as ''[[S. cerevisiae]]'', ''D.melanogaster'' and ''[[Caenorhabditis elegans|C. elegans]]'' have shown that PTC recognition involving [[invertebrate]] organisms does not involve exon-exon boundaries.<ref name="Behm" /> These studies suggest that invertebrate NMD occurs independently of splicing. As a result, EJCs which are responsible for marking exon-exon boundaries are not required in invertebrate NMD.<ref name="Amrani2" /> Several models have been proposed to explain how PTCs are distinguished from normal stop codons in invertebrates. One of these suggests that there may be a downstream sequence element which functions similar to the exon junctions in mammals.<ref name="Conti" /> A second model proposes that a widely present feature in mRNA, such as a 3' poly-A tail, might provide the positional information required for recognition.<ref name="Palaniswamy">{{cite journal | last1 = Palaniswamy | first1 = V. | last2 = Moraes | first2 = K.C. | last3 = Wilusz | first3 = C.J. | last4 = Wilusz | first4 = J. | year = 2006 | title = Nucleophosmin is selectively deposited on mRNA during polyadenylation | url = | journal = Nat. Struct. Mol. Biol. | volume = 13 | issue = | pages = 429–435 | doi=10.1038/nsmb1080}}</ref> Another model, dubbed the "faux 3'UTR model", suggests that premature translation termination may be distinguished from normal termination because of intrinsic features that may allow it to recognize its presence in an inappropriate environment.<ref name="Amrani2" /> These mechanisms, however, have yet to be conclusively demonstrated.
Studies involving organisms such as ''[[S. cerevisiae]]'', ''D.melanogaster'' and ''[[Caenorhabditis elegans|C. elegans]]'' have shown that PTC recognition involving [[invertebrate]] organisms does not involve exon-exon boundaries.<ref name="Behm" /> These studies suggest that invertebrate NMD occurs independently of splicing. As a result, EJCs which are responsible for marking exon-exon boundaries are not required in invertebrate NMD.<ref name="Amrani2" /> Several models have been proposed to explain how PTCs are distinguished from normal stop codons in invertebrates. One of these suggests that there may be a downstream sequence element which functions similar to the exon junctions in mammals.<ref name="Conti" /> A second model proposes that a widely present feature in mRNA, such as a 3' poly-A tail, might provide the positional information required for recognition.<ref name="Palaniswamy">{{cite journal | vauthors = Palaniswamy V, Moraes KC, Wilusz CJ, Wilusz J | title = Nucleophosmin is selectively deposited on mRNA during polyadenylation | journal = Nature Structural & Molecular Biology | volume = 13 | issue = 5 | pages = 429–35 | date = May 2006 | pmid = 16604083 | doi = 10.1038/nsmb1080 }}</ref> Another model, dubbed the "faux 3'UTR model", suggests that premature translation termination may be distinguished from normal termination because of intrinsic features that may allow it to recognize its presence in an inappropriate environment.<ref name="Amrani2" /> These mechanisms, however, have yet to be conclusively demonstrated.


=== Mechanism in plants ===
=== Mechanism in plants ===
There are two mechanisms of PTC recognition in plants: according to its distance from the EJC (like in vertebrates) or from the poly-A tail. The NMD mechanism in plants induces the decay of mRNAs containing a 3’NTR longer than 300 nt, that is why the proportion of mRNAs with longer 3'NTRs is much lower in plants than in vertebrates.<ref>{{Cite journal|last=Schwartz|first=A. M.|last2=Komarova|first2=T. V.|last3=Skulachev|first3=M. V.|last4=Zvereva|first4=A. S.|last5=Dorokhov|first5=Iu L.|last6=Atabekov|first6=J. G.|date=2006-12-01|title=Stability of plant mRNAs depends on the length of the 3'-untranslated region|journal=Biochemistry. Biokhimiia|volume=71|issue=12|pages=1377–1384|issn=0006-2979|pmid=17223792|doi=10.1134/s0006297906120145}}</ref><ref>{{Cite journal|last=Nyikó|first=Tünde|last2=Kerényi|first2=Farkas|last3=Szabadkai|first3=Levente|last4=Benkovics|first4=Anna H.|last5=Major|first5=Péter|last6=Sonkoly|first6=Boglárka|last7=Mérai|first7=Zsuzsanna|last8=Barta|first8=Endre|last9=Niemiec|first9=Emilia|date=2013-07-01|title=Plant nonsense-mediated mRNA decay is controlled by different autoregulatory circuits and can be induced by an EJC-like complex|url=https://academic.oup.com/nar/article/41/13/6715/1127021/Plant-nonsense-mediated-mRNA-decay-is-controlled|journal=Nucleic Acids Research|volume=41|issue=13|pages=6715–6728|doi=10.1093/nar/gkt366|issn=0305-1048|pmc=3711448|pmid=23666629}}</ref>
There are two mechanisms of PTC recognition in plants: according to its distance from the EJC (like in vertebrates) or from the poly-A tail. The NMD mechanism in plants induces the decay of mRNAs containing a 3’NTR longer than 300 nt, that is why the proportion of mRNAs with longer 3'NTRs is much lower in plants than in vertebrates.<ref>{{cite journal | vauthors = Schwartz AM, Komarova TV, Skulachev MV, Zvereva AS, Dorokhov I, Atabekov JG | title = Stability of plant mRNAs depends on the length of the 3'-untranslated region | journal = Biochemistry. Biokhimiia | volume = 71 | issue = 12 | pages = 1377–84 | date = December 2006 | pmid = 17223792 | doi = 10.1134/s0006297906120145 }}</ref><ref>{{cite journal | vauthors = Nyikó T, Kerényi F, Szabadkai L, Benkovics AH, Major P, Sonkoly B, Mérai Z, Barta E, Niemiec E, Kufel J, Silhavy D | title = Plant nonsense-mediated mRNA decay is controlled by different autoregulatory circuits and can be induced by an EJC-like complex | journal = Nucleic Acids Research | volume = 41 | issue = 13 | pages = 6715–28 | date = July 2013 | pmid = 23666629 | pmc = 3711448 | doi = 10.1093/nar/gkt366 | url = https://academic.oup.com/nar/article/41/13/6715/1127021/Plant-nonsense-mediated-mRNA-decay-is-controlled }}</ref>


=== NMD avoidance ===
=== NMD avoidance ===
mRNAs with nonsense mutations are generally thought to be targeted for decay via the NMD pathways. The presence of this premature stop codon about 50-54 nts 5' to the exon junction appears to be the trigger for rapid decay; however, it has been observed that some mRNA molecules with a premature stop codon are able to avoid detection and decay.<ref name="Nagy" /><ref name="Ina">{{cite journal | last1 = Inácio | first1 = A. | last2 = Silva | first2 = A.L. | last3 = Pinto | first3 = J. | last4 = Ji | first4 = X. | last5 = Morgado | first5 = A. | last6 = Almeida | first6 = F. | last7 = Faustino | first7 = P. | last8 = Lavinha | first8 = J. | last9 = Liebhaber | first9 = S.A. | last10 = Romão | first10 = L. | year = 2004 | title = Nonsense mutations in close proximity to the initiation codon fail to trigger full nonsense-mediated mRNA decay | url = | journal = J. Biol. Chem. | volume = 279 | issue = | pages = 32170–32180 | doi=10.1074/jbc.m405024200}}</ref> In general, these mRNA molecules possess the stop codon very early in the reading frame (i.e. the PTC is AUG-proximal). This appears to be a contradiction to the current accepted model of NMD as this position is significantly 5' of the exon-exon junction.<ref name= "Silva2006">{{cite journal | last1 = Silva | first1 = A.L. | last2 = Pereira | first2 = F.J. | last3 = Morgado | first3 = A. | last4 = Kong | first4 = J. | last5 = Martins | first5 = R. | last6 = Faustino | first6 = P. | last7 = Liebhaber | first7 = S.A. | last8 = Romão | first8 = L. | year = 2006 | title = The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context | url = | journal = RNA | volume = 12 | issue = | pages = 2160–2170 | doi=10.1261/rna.201406}}</ref>
mRNAs with nonsense mutations are generally thought to be targeted for decay via the NMD pathways. The presence of this premature stop codon about 50-54 nts 5' to the exon junction appears to be the trigger for rapid decay; however, it has been observed that some mRNA molecules with a premature stop codon are able to avoid detection and decay.<ref name="Nagy" /><ref name="Ina">{{cite journal | vauthors = Inácio A, Silva AL, Pinto J, Ji X, Morgado A, Almeida F, Faustino P, Lavinha J, Liebhaber SA, Romão L | title = Nonsense mutations in close proximity to the initiation codon fail to trigger full nonsense-mediated mRNA decay | journal = The Journal of Biological Chemistry | volume = 279 | issue = 31 | pages = 32170–80 | date = July 2004 | pmid = 15161914 | doi = 10.1074/jbc.m405024200 }}</ref> In general, these mRNA molecules possess the stop codon very early in the reading frame (i.e. the PTC is AUG-proximal). This appears to be a contradiction to the current accepted model of NMD as this position is significantly 5' of the exon-exon junction.<ref name= "Silva2006">{{cite journal | vauthors = Silva AL, Pereira FJ, Morgado A, Kong J, Martins R, Faustino P, Liebhaber SA, Romão L | title = The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context | journal = Rna | volume = 12 | issue = 12 | pages = 2160–70 | date = December 2006 | pmid = 17077274 | doi = 10.1261/rna.201406 }}</ref>


This has been demonstrated in β-globulin. β-globulin mRNAs containing a nonsense mutation early in the first exon of the gene are more stable than NMD sensitive mRNA molecules. The exact mechanism of detection avoidance is currently not known. It has been suggested that the poly-A binding protein (PABP) appears to play a role in this stability.<ref name="Silva2008">{{cite journal | last1 = Silva | first1 = A.L. | last2 = Ribeiro | first2 = P. | last3 = Liebhaber | first3 = S.A. | last4 = Romao | first4 = L. | year = 2008 | title = Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay | url = | journal = RNA | volume = 14 | issue = | pages = 563–576 | doi=10.1261/rna.815108}}</ref> It has been demonstrated in other studies that the presence of this protein near AUG-proximal PTCs appears to promote the stability of these otherwise NMD sensitive mRNAs. It has been observed that this protective effect is not limited only to the β-globulin promoter.<ref name="Ina" /> This suggests that this NMD avoidance mechanism may be prevalent in other tissue types for a variety of genes. The current model of NMD may need to be revisited upon further studies.
This has been demonstrated in β-globulin. β-globulin mRNAs containing a nonsense mutation early in the first exon of the gene are more stable than NMD sensitive mRNA molecules. The exact mechanism of detection avoidance is currently not known. It has been suggested that the poly-A binding protein (PABP) appears to play a role in this stability.<ref name="Silva2008">{{cite journal | vauthors = Silva AL, Ribeiro P, Inácio A, Liebhaber SA, Romão L | title = Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay | journal = Rna | volume = 14 | issue = 3 | pages = 563–76 | date = March 2008 | pmid = 18230761 | doi = 10.1261/rna.815108 }}</ref> It has been demonstrated in other studies that the presence of this protein near AUG-proximal PTCs appears to promote the stability of these otherwise NMD sensitive mRNAs. It has been observed that this protective effect is not limited only to the β-globulin promoter.<ref name="Ina" /> This suggests that this NMD avoidance mechanism may be prevalent in other tissue types for a variety of genes. The current model of NMD may need to be revisited upon further studies.


==Nonstop mediated mRNA decay==
==Nonstop mediated mRNA decay==
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===Overview===
===Overview===
[[Image:nonstopdecayrevised.jpg|thumb|400px|Nonstop mediated mRNA. Translation of a mRNA without a stop codon results in the translation of the ribosome into the 3' poly-A tail region. this results in a stalled ribosome. The ribosome is rescued by two distinct pathways. The mechanisms are dependent of the absence or presence of the Ski7 protein.<ref name="Garneau!">Garneau NL, Wilusz J, Wilusz CJ: The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 2007, 8:113-126.</ref>]]
[[Image:nonstopdecayrevised.jpg|thumb|400px|Nonstop mediated mRNA. Translation of a mRNA without a stop codon results in the translation of the ribosome into the 3' poly-A tail region. this results in a stalled ribosome. The ribosome is rescued by two distinct pathways. The mechanisms are dependent of the absence or presence of the Ski7 protein.<ref name="Garneau!">{{cite journal | vauthors = Garneau NL, Wilusz J, Wilusz CJ | title = The highways and byways of mRNA decay | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 2 | pages = 113–26 | date = February 2007 | pmid = 17245413 | doi = 10.1038/nrm2104 }}</ref>]]


Nonstop mediated decay (NSD) is involved in the detection and decay of mRNA transcripts which lack a stop codon.<ref name="vanhoof1">van Hoof, A., Frischmeyer, P. A., Dietz, H. C. & Parker, R. Exosome-mediated recognition and degradation of mRNAs lacking a termination codon. Science 295, 2262–2264 (2002).</ref><ref name="frischmeyer">{{cite journal | last1 = Frischmeyer | first1 = P. A. |display-authors=etal | year = 2002 | title = An mRNA surveillance mechanism that eliminates transcripts lacking termination codons | url = | journal = Science | volume = 295 | issue = | pages = 2258–2261 | doi=10.1126/science.1067338}}</ref> These mRNA transcripts can arise from many different mechanisms such as premature 3' adenylation or cryptic polyadenylation signals within the coding region of a gene.<ref name="Temperly">{{cite journal | last1 = Temperley | first1 = RJ | last2 = Seneca | first2 = SH | last3 = Tonska | first3 = K | last4 = Bartnik | first4 = E | last5 = Bindoff | first5 = LA | last6 = Lightowlers | first6 = RN | last7 = Chrzanowska-Lightowlers | first7 = ZM | year = 2003 | title = Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria | url = | journal = Hum Mol Genet | volume = 12 | issue = | pages = 2341–2348 | doi=10.1093/hmg/ddg238}}</ref> This lack of a stop codon results a significant issue for cells. Ribosomes translating the mRNA eventually translate into the 3'poly-A tail region of transcripts and stalls. As a result, it cannot eject the mRNA.<ref>{{cite journal | last1 = Karzai | first1 = AW | last2 = Roche | first2 = ED | last3 = Sauer | first3 = RT | year = 2000 | title = The SsrA-SmpB system for protein tagging, directed degradation and ribosome rescue | url = | journal = Nat Struct Biol | volume = 7 | issue = | pages = 449–455 }}</ref> Ribosomes thus may become sequestered associated with the nonstop mRNA and would not be available to translate other mRNA molecules into proteins. Nonstop mediated decay resolves this problem by both freeing the stalled ribosomes and marking the nonstop mRNA for degradation in the cell by nucleases. Nonstop mediated decay consists of two distinct pathways which likely act in concert to decay nonstop mRNA.<ref name="vanhoof1" /><ref name="frischmeyer" />
Nonstop mediated decay (NSD) is involved in the detection and decay of mRNA transcripts which lack a stop codon.<ref name="vanhoof1">van Hoof, A., Frischmeyer, P. A., Dietz, H. C. & Parker, R. Exosome-mediated recognition and degradation of mRNAs lacking a termination codon. Science 295, 2262–2264 (2002).</ref><ref name="frischmeyer">{{cite journal | vauthors = Frischmeyer PA, van Hoof A, O'Donnell K, Guerrerio AL, Parker R, Dietz HC | title = An mRNA surveillance mechanism that eliminates transcripts lacking termination codons | journal = Science | volume = 295 | issue = 5563 | pages = 2258–61 | date = March 2002 | pmid = 11910109 | doi = 10.1126/science.1067338 }}</ref> These mRNA transcripts can arise from many different mechanisms such as premature 3' adenylation or cryptic polyadenylation signals within the coding region of a gene.<ref name="Temperly">{{cite journal | vauthors = Temperley RJ, Seneca SH, Tonska K, Bartnik E, Bindoff LA, Lightowlers RN, Chrzanowska-Lightowlers ZM | title = Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria | journal = Human Molecular Genetics | volume = 12 | issue = 18 | pages = 2341–8 | date = September 2003 | pmid = 12915481 | doi = 10.1093/hmg/ddg238 }}</ref> This lack of a stop codon results a significant issue for cells. Ribosomes translating the mRNA eventually translate into the 3'poly-A tail region of transcripts and stalls. As a result, it cannot eject the mRNA.<ref>{{cite journal | vauthors = Karzai AW, Roche ED, Sauer RT | title = The SsrA-SmpB system for protein tagging, directed degradation and ribosome rescue | journal = Nature Structural Biology | volume = 7 | issue = 6 | pages = 449–55 | date = June 2000 | pmid = 10881189 | doi = 10.1038/75843 }}</ref> Ribosomes thus may become sequestered associated with the nonstop mRNA and would not be available to translate other mRNA molecules into proteins. Nonstop mediated decay resolves this problem by both freeing the stalled ribosomes and marking the nonstop mRNA for degradation in the cell by nucleases. Nonstop mediated decay consists of two distinct pathways which likely act in concert to decay nonstop mRNA.<ref name="vanhoof1" /><ref name="frischmeyer" />


===Ski7 pathway===
===Ski7 pathway===
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==No-Go decay==
==No-Go decay==
[[Image:Endonucleolyticcleavage.jpg|thumb|left|400px|No-Go Mediated mRNA decay.]]
[[Image:Endonucleolyticcleavage.jpg|thumb|left|400px|No-Go Mediated mRNA decay.]]
No-Go decay (NGD) is the most recently discovered surveillance mechanism.<ref name="Doman">Doma, M. K. & Parker, R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature 440, 561–564.(2006).</ref> As such, it is not currently well understood. While authentic targets of NGD are poorly understood, they appear to consist largely of mRNA transcripts on which ribosomes have stalled during translation. This stall can be caused by a variety of factors including strong [[secondary structure]]s, which may physically block the translational machinery from moving down the transcript.<ref name="Doman" /> Dom34/Hbs1 likely binds near the A site of stalled ribosomes and may facilitate recycling of complexes.<ref name="Kobayashi">Kobayashi K, Kikuno I, Kuroha K, Saito K, Ito K, Ishitani R, Inada T, & Nureki O. Structural basis for mRNA surveillance by archaeal Pelota and GTP-bound EF1α complex. PNAS. 107(41):17575-9. (2010).</ref> In some cases, the transcript is also cleaved in an endonucleolytic fashion near the stall site; however the identity of the responsible endonuclease remains contentious. The [[Fragmentation (cell biology)|fragmented]] mRNA molecules are then fully degraded by the exosome in a 3' to 5' fashion and by Xrn1 in a 5' to 3' fashion.<ref name="Doman" />
No-Go decay (NGD) is the most recently discovered surveillance mechanism.<ref name="Doman">{{cite journal | vauthors = Doma MK, Parker R | title = Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation | journal = Nature | volume = 440 | issue = 7083 | pages = 561–4 | date = March 2006 | pmid = 16554824 | pmc = 1839849 | doi = 10.1038/nature04530 }}</ref> As such, it is not currently well understood. While authentic targets of NGD are poorly understood, they appear to consist largely of mRNA transcripts on which ribosomes have stalled during translation. This stall can be caused by a variety of factors including strong [[secondary structure]]s, which may physically block the translational machinery from moving down the transcript.<ref name="Doman" /> Dom34/Hbs1 likely binds near the A site of stalled ribosomes and may facilitate recycling of complexes.<ref name="Kobayashi">{{cite journal | vauthors = Kobayashi K, Kikuno I, Kuroha K, Saito K, Ito K, Ishitani R, Inada T, Nureki O | title = Structural basis for mRNA surveillance by archaeal Pelota and GTP-bound EF1α complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 41 | pages = 17575–9 | date = October 2010 | pmid = 20876129 | pmc = 2955123 | doi = 10.1073/pnas.1009598107 }}</ref> In some cases, the transcript is also cleaved in an endonucleolytic fashion near the stall site; however the identity of the responsible endonuclease remains contentious. The [[Fragmentation (cell biology)|fragmented]] mRNA molecules are then fully degraded by the exosome in a 3' to 5' fashion and by Xrn1 in a 5' to 3' fashion.<ref name="Doman" />
It is not currently known how this process releases the mRNA from the ribosomes, however, Hbs1 is closely related to the Ski7 protein which plays a clear role in ribosome release in Ski7 mediated NSD. It is postulated that Hbs1 may play a similar role in NGD.<ref name="jebus" /><ref>Graille M, Chaillet M, van Tilbeurgh H. Structure of yeast Dom34: a protein related to translation termination factor eRF1 and involved in No-Go decay. J Biol Chem. 2008;283:7145–7154.</ref>
It is not currently known how this process releases the mRNA from the ribosomes, however, Hbs1 is closely related to the Ski7 protein which plays a clear role in ribosome release in Ski7 mediated NSD. It is postulated that Hbs1 may play a similar role in NGD.<ref name="jebus" /><ref name="pmid18180287">{{cite journal | vauthors = Graille M, Chaillet M, van Tilbeurgh H | title = Structure of yeast Dom34: a protein related to translation termination factor Erf1 and involved in No-Go decay | journal = The Journal of Biological Chemistry | volume = 283 | issue = 11 | pages = 7145–54 | date = March 2008 | pmid = 18180287 | doi = 10.1074/jbc.M708224200 }}</ref>


==Evolution==
==Evolution==


It is possible to determine the [[evolutionary]] history of these mechanisms by observing the conservation of key proteins implicated in each mechanism. For example: Dom34/Hbs1 are associated with NGD;<ref name="Doman"/> Ski7 is associated with NSD;<ref name="vanhoof1" /> and the eRF proteins are associated with NMD.<ref name="Rehwinkel" /> To this end, extensive [[BLAST]] searches have been performed to determine the prevalence of the proteins in various types of organisms. It has been determined that NGD Hbs1 and NMD eRF3 are found only in eukaryotes. However, the NGD Dom34 is universal in eukaryotes and [[archaea]]. This suggests that NGD appears to have been the first evolved mRNA surveillance mechanism. The NSD Ski7 protein appears to be restricted strictly to yeast species which suggest that NSD is the most recently evolved surveillance mechanism. This by default leaves NMD as the second evolved surveillance mechanism.<ref name="Atkinsonz">Atkinson GC, Baldauf SL, Hauryliuk V. Evolution of nonstop, no-go and nonsense-mediated mRNA decay and their termination factor-derived components. BMC Evol Biol. 2008 Oct 23;8:290</ref>
It is possible to determine the [[evolutionary]] history of these mechanisms by observing the conservation of key proteins implicated in each mechanism. For example: Dom34/Hbs1 are associated with NGD;<ref name="Doman"/> Ski7 is associated with NSD;<ref name="vanhoof1" /> and the eRF proteins are associated with NMD.<ref name="Rehwinkel" /> To this end, extensive [[BLAST]] searches have been performed to determine the prevalence of the proteins in various types of organisms. It has been determined that NGD Hbs1 and NMD eRF3 are found only in eukaryotes. However, the NGD Dom34 is universal in eukaryotes and [[archaea]]. This suggests that NGD appears to have been the first evolved mRNA surveillance mechanism. The NSD Ski7 protein appears to be restricted strictly to yeast species which suggest that NSD is the most recently evolved surveillance mechanism. This by default leaves NMD as the second evolved surveillance mechanism.<ref name="Atkinsonz">{{cite journal | vauthors = Atkinson GC, Baldauf SL, Hauryliuk V | title = Evolution of nonstop, no-go and nonsense-mediated mRNA decay and their termination factor-derived components | journal = BMC Evolutionary Biology | volume = 8 | issue = | pages = 290 | date = October 2008 | pmid = 18947425 | doi = 10.1186/1471-2148-8-290 }}</ref>


[[File:wikipedia6.jpg|thumb|500px|A proposed evolutionary mechanism for development of mRNA surveillance component proteins.<ref name="Atkinsonz" />]]
[[File:wikipedia6.jpg|thumb|500px|A proposed evolutionary mechanism for development of mRNA surveillance component proteins.<ref name="Atkinsonz" />]]
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{{reflist|30em}}
{{reflist|30em}}


==External links==
== External links ==
*[https://web.archive.org/web/20090908223156/http://scienceblogs.com/transcript/2006/04/no-go_decay.php The Daily Transcript: No-go Decay]
*[https://web.archive.org/web/20090908223156/http://scienceblogs.com/transcript/2006/04/no-go_decay.php The Daily Transcript: No-go Decay]
*[http://chemistryolife.blogspot.com/2007/12/nonstop-decay.html Chemistry of Life: non stop decay]
*[http://chemistryolife.blogspot.com/2007/12/nonstop-decay.html Chemistry of Life: non stop decay]

Revision as of 17:28, 17 February 2019

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

Overview

The translation of messenger RNA transcripts into proteins is a vital part of the central dogma of molecular biology. mRNA molecules are, however, prone to a host of fidelity errors which can cause errors in translation of mRNA into quality proteins.[1] RNA surveillance mechanisms are methods cells use to assure the quality and fidelity of the mRNA molecules.[2] This is generally achieved through marking aberrant mRNA molecule for degradation by various endogenous nucleases.[3]

mRNA surveillance has been documented in bacteria and yeast. In eukaryotes, these mechanisms are known to function in both the nucleus and cytoplasm.[4] Fidelity checks of mRNA molecules in the nucleus results in the degradation of improperly processed transcripts before export into the cytoplasm. Transcripts are subject to further surveillance once in the cytoplasm. Cytoplasmic surveillance mechanisms assess mRNA transcripts for the absence of or presence of premature stop codons.[3][4]

Three surveillance mechanisms are currently known to function within cells: the nonsense-mediated mRNA decay pathway (NMD); the nonstop mediated mRNA decay pathways (NSD); and the no-go mediated mRNA decay pathway (NGD).

Nonsense-mediated mRNA decay

Main article: Nonsense-mediated decay
UPF1 is a conserved helicase which is phosphorylated in the process of NMD. This phosphorylation is catalyzed by SMG1 kinase. This process requires UPF2 and UPF3. Dephosphorylation of UPF1 is catalyzed by SMG5, SMG6 and SMG7 proteins.[5]

Overview

Nonsense-mediated decay is involved in detection and decay of mRNA transcripts which contain premature termination codons (PTCs). PTCs can arise in cells through various mechanisms: germline mutations in DNA; somatic mutations in DNA; errors in transcription; or errors in post transcriptional mRNA processing.[5][6] Failure to recognize and decay these mRNA transcripts can result in the production of truncated proteins which may be harmful to the organism. By causing decay of C-terminally truncated polypeptides, the NMD mechanism can protect cells against deleterious dominant-negative, and gain of function effects.[7] PTCs have been implicated in approximately 30% of all inherited diseases; as such, the NMD pathway plays a vital role in assuring overall survival and fitness of an organism[8][9]

A surveillance complex consisting of various proteins (eRF1, eRF3, Upf1, Upf2 and Upf3) is assembled and scans the mRNA for premature stop codons.[5] The assembly of this complex is triggered by premature translation termination. If a premature stop codon is detected then the mRNA transcript is signalled for degradation – the coupling of detection with degradation occurs.[3][10][11]

Seven smg genes (smg1-7) and three UPF genes (Upf1-3) have been identified in Saccharomyces cerevisiae and Caenorhabditis elegans as essential trans-acting factors contributing to NMD activity.[12][13] All of these genes are conserved in Drosophila melanogaster and further mammals where they also play critical roles in NMD. Throughout eukaryotes there are three components which are conserved in the process of NMD.[14] These are the Upf1/SMG-2, Upf2/SMG-3 and Upf3/SMG-4 complexes. Upf1/SMG-2 is a phosphoprotein in multicellular organisms and is thought to contribute to NMD via its phosphorylation activity. However, the exact interactions of the proteins and their roles in NMD are currently disputed.[11][12][14][15][16]

Mechanism in mammals

Nonsense mediated decay in mammals is mediated by the exon-exon junction. This junction is marked by a group of proteins which constitute the exon junction complex (EJC). The EJC recruits UPF1/SMG by transcription factors eRF1/eRF3. Interactions of these proteins lead to the assembly of the surveillance complex. This complex is ultimately responsible for the degradation of the nonsense mRNA.[5]

A premature stop codon must be recognized as different from a normal stop codon so that only the former triggers a NMD response. It has been observed that the ability of a nonsense codon to cause mRNA degradation depends on its relative location to the downstream sequence element and associated proteins.[1] Studies have demonstrated that nucleotides more than 50–54 nucleotides upstream of the last exon-exon junction can target mRNA for decay.[1][4][5][6][7][17] Those downstream from this region are unable to do so. Thus, nonsense codons lie more than 50-54 nucleotides upstream from the last exon boundary whereas natural stop codons are located within terminal exons.[18] Exon junction complexes (EJCs) mark the exon-exon boundaries. EJCs are multiprotein complexes that assemble during splicing at a position about 20–24 nucleotides upstream from the splice junction.[19] It is this EJC that provides position information needed to discriminate premature stop codons from natural stop codons. Recognition of PTCs appears to be dependent on the definitions of the exon-exon junctions. This suggests involvement of the spliceosome in mammalian NMD.[17][20] Research has investigated the possibility of spliceosome involvement in mammalian NMD and has determined this is a likely possibility.[18] Furthermore, it has been observed that NMD mechanisms are not activated by nonsense transcripts that are generated from genes that naturally do not contain introns (i.e. Histone H4, Hsp70, melanocortin-4-receptor).[7]

When the ribosome reaches a PTC the translation factors eRF1 and eRF3 interact with retained EJC complexes though a multiprotein bridge.[21] The interactions of UPF1 with the terminating complex and with UPF2/UPF3 of the retained EJCs are critical. It is these interactions which target the mRNA for rapid decay by endogenous nucleases[18][21]

Nonsense mediated mRNA decay in invertebrates is postulated to be mediated by the presence of a faux 3' untranslated region (UTR). These faux 3'UTRs are distinguished from natural 3'UTRs which follow natural stop codons. This is due to the lack of binding proteins which are normally present in natural 3'UTR. These binding proteins include the poly(A)-binding protein (PABP).[5]

Mechanism in invertebrates

Studies involving organisms such as S. cerevisiae, D.melanogaster and C. elegans have shown that PTC recognition involving invertebrate organisms does not involve exon-exon boundaries.[20] These studies suggest that invertebrate NMD occurs independently of splicing. As a result, EJCs which are responsible for marking exon-exon boundaries are not required in invertebrate NMD.[3] Several models have been proposed to explain how PTCs are distinguished from normal stop codons in invertebrates. One of these suggests that there may be a downstream sequence element which functions similar to the exon junctions in mammals.[11] A second model proposes that a widely present feature in mRNA, such as a 3' poly-A tail, might provide the positional information required for recognition.[22] Another model, dubbed the "faux 3'UTR model", suggests that premature translation termination may be distinguished from normal termination because of intrinsic features that may allow it to recognize its presence in an inappropriate environment.[3] These mechanisms, however, have yet to be conclusively demonstrated.

Mechanism in plants

There are two mechanisms of PTC recognition in plants: according to its distance from the EJC (like in vertebrates) or from the poly-A tail. The NMD mechanism in plants induces the decay of mRNAs containing a 3’NTR longer than 300 nt, that is why the proportion of mRNAs with longer 3'NTRs is much lower in plants than in vertebrates.[23][24]

NMD avoidance

mRNAs with nonsense mutations are generally thought to be targeted for decay via the NMD pathways. The presence of this premature stop codon about 50-54 nts 5' to the exon junction appears to be the trigger for rapid decay; however, it has been observed that some mRNA molecules with a premature stop codon are able to avoid detection and decay.[17][25] In general, these mRNA molecules possess the stop codon very early in the reading frame (i.e. the PTC is AUG-proximal). This appears to be a contradiction to the current accepted model of NMD as this position is significantly 5' of the exon-exon junction.[26]

This has been demonstrated in β-globulin. β-globulin mRNAs containing a nonsense mutation early in the first exon of the gene are more stable than NMD sensitive mRNA molecules. The exact mechanism of detection avoidance is currently not known. It has been suggested that the poly-A binding protein (PABP) appears to play a role in this stability.[27] It has been demonstrated in other studies that the presence of this protein near AUG-proximal PTCs appears to promote the stability of these otherwise NMD sensitive mRNAs. It has been observed that this protective effect is not limited only to the β-globulin promoter.[25] This suggests that this NMD avoidance mechanism may be prevalent in other tissue types for a variety of genes. The current model of NMD may need to be revisited upon further studies.

Nonstop mediated mRNA decay

Main article: Non-stop decay

Overview

Nonstop mediated mRNA. Translation of a mRNA without a stop codon results in the translation of the ribosome into the 3' poly-A tail region. this results in a stalled ribosome. The ribosome is rescued by two distinct pathways. The mechanisms are dependent of the absence or presence of the Ski7 protein.[28]

Nonstop mediated decay (NSD) is involved in the detection and decay of mRNA transcripts which lack a stop codon.[29][30] These mRNA transcripts can arise from many different mechanisms such as premature 3' adenylation or cryptic polyadenylation signals within the coding region of a gene.[31] This lack of a stop codon results a significant issue for cells. Ribosomes translating the mRNA eventually translate into the 3'poly-A tail region of transcripts and stalls. As a result, it cannot eject the mRNA.[32] Ribosomes thus may become sequestered associated with the nonstop mRNA and would not be available to translate other mRNA molecules into proteins. Nonstop mediated decay resolves this problem by both freeing the stalled ribosomes and marking the nonstop mRNA for degradation in the cell by nucleases. Nonstop mediated decay consists of two distinct pathways which likely act in concert to decay nonstop mRNA.[29][30]

Ski7 pathway

This pathway is active when Ski7 protein is available in the cell. The Ski7 protein is thought to bind to the empty A site of the ribosome. This binding allows the ribosome to eject the stuck nonstop mRNA molecule – this even frees the ribosome and allows it to translate other transcripts. The Ski7 is now associated with the nonstop mRNA and it is this association which targets the nonstop mRNA for recognition by the cytosolic exosome. The Ski7-exosome complex rapidly deadenylates the mRNA molecule which allows the exosome to decay the transcript in a 3' to 5' fashion.[29][30]

Non-Ski7 pathway

A second type of NSD has been observed in yeast. In this mechanism, the absence of Ski7 results in the loss of poly-A tail binding PABP proteins by the action of the translation ribosome. The removal of these PABP proteins then results in the loss of the protective 5'm7G cap. The loss of the cap results in rapid degradation of the transcript by an endogenous 5'-3' exonuclease such as XrnI.[30]

No-Go decay

No-Go Mediated mRNA decay.

No-Go decay (NGD) is the most recently discovered surveillance mechanism.[33] As such, it is not currently well understood. While authentic targets of NGD are poorly understood, they appear to consist largely of mRNA transcripts on which ribosomes have stalled during translation. This stall can be caused by a variety of factors including strong secondary structures, which may physically block the translational machinery from moving down the transcript.[33] Dom34/Hbs1 likely binds near the A site of stalled ribosomes and may facilitate recycling of complexes.[34] In some cases, the transcript is also cleaved in an endonucleolytic fashion near the stall site; however the identity of the responsible endonuclease remains contentious. The fragmented mRNA molecules are then fully degraded by the exosome in a 3' to 5' fashion and by Xrn1 in a 5' to 3' fashion.[33] It is not currently known how this process releases the mRNA from the ribosomes, however, Hbs1 is closely related to the Ski7 protein which plays a clear role in ribosome release in Ski7 mediated NSD. It is postulated that Hbs1 may play a similar role in NGD.[5][35]

Evolution

It is possible to determine the evolutionary history of these mechanisms by observing the conservation of key proteins implicated in each mechanism. For example: Dom34/Hbs1 are associated with NGD;[33] Ski7 is associated with NSD;[29] and the eRF proteins are associated with NMD.[6] To this end, extensive BLAST searches have been performed to determine the prevalence of the proteins in various types of organisms. It has been determined that NGD Hbs1 and NMD eRF3 are found only in eukaryotes. However, the NGD Dom34 is universal in eukaryotes and archaea. This suggests that NGD appears to have been the first evolved mRNA surveillance mechanism. The NSD Ski7 protein appears to be restricted strictly to yeast species which suggest that NSD is the most recently evolved surveillance mechanism. This by default leaves NMD as the second evolved surveillance mechanism.[36]

A proposed evolutionary mechanism for development of mRNA surveillance component proteins.[36]

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External links

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