Editing Stop codon

{{short description|Codon that marks the end of a protein-coding sequence}}
[[File:Homo sapiens-mtDNA~NC 012920-ATP8+ATP6 Overlap.svg|thumb|right|400px|Stop codon (red dot) of the human mitochondrial DNA ''MT-ATP8'' gene, and start codon (blue circle) of the ''MT-ATP6'' gene. For each nucleotide triplet (square brackets), the corresponding amino acid is given (one-letter code), either in the +1 [[reading frame]] for ''MT-ATP8'' (in red) or in the +3 frame for ''MT-ATP6'' (in blue). In this genomic region, the two genes [[Overlapping gene|overlap]].]]

In [[molecular biology]], a '''stop codon''' (or '''termination codon''') is a [[Genetic code|codon]] ([[nucleotide]] triplet within [[messenger RNA]]) that signals the termination of the [[translation (biology)|translation]] process of the current [[protein]].<ref>{{cite book|vauthors=((Griffiths AJF)), Miller JH, Suzuki DT, Lewontin RC, Gelbart WM | title=An Introduction to Genetic Analysis| year=2000| publisher=W.H. Freeman |chapter=10. Molecular Biology of Gene Function: Genetic code: §Stop codons |isbn=978-0-7167-3520-5 |oclc=42049331 |edition=7th}}</ref> Most codons in messenger RNA correspond to the addition of an [[amino acid]] to a growing [[polypeptide]] chain, which may ultimately become a protein; stop codons signal the termination of this process by binding [[release factor]]s, which cause the [[Ribosome|ribosomal]] subunits to disassociate, releasing the amino acid chain.

While [[start codon]]s need nearby sequences or [[initiation factor]]s to start translation, a stop codon alone is sufficient to initiate termination.

== Properties ==
=== Standard codons ===
In the standard genetic code, there are three different termination codons:

{|class="wikitable" style="border: none; text-align: center;"
|-
! colspan="2" | Codon
! rowspan="2" | [[DNA codon table|Standard code]]<br>(Translation table 1)
! rowspan="2" style="border:none; width:1px;" |
! rowspan="2" | Name
|-
! DNA
! RNA
|-
| <code>TAG</code> || <code>UAG</code>
| style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code>
| style="border: none; width: 1px;" |
| style="background-color: none;" | "amber"
|-
| <code>TAA</code> || <code>UAA</code>
| style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code>
| style="border: none; width: 1px;" |
| style="background-color: none;" | "ochre"
|-
| <code>TGA</code> || <code>UGA</code>
| style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code>
| style="border: none; width: 1px;" |
| style="background-color: none;" | "opal" (or "umber")
|}

=== Alternative stop codons ===
There are [[Genetic code#Variations|variations on the standard genetic code]], and alternative stop codons have been found in the [[Mitochondrial DNA|mitochondrial genome]]s of [[vertebrate]]s,<ref>{{Cite journal |last1=Barrell |first1=B. G. |last2=Bankier |first2=A. T. |last3=Drouin |first3=J. |date=1979-11-08 |title=A different genetic code in human mitochondria |url=http://www.nature.com/articles/282189a0 |journal=Nature |language=en |volume=282 |issue=5735 |pages=189–194 |doi=10.1038/282189a0 |pmid=226894 |bibcode=1979Natur.282..189B |s2cid=4335828 |issn=0028-0836|url-access=subscription }}</ref> ''[[Scenedesmus obliquus]]'',<ref name="Nedelcu2000">{{Cite journal |journal=Genome Research |date=June 2000 |volume=10 |issue=6 |pages=819–831 |title=The complete mitochondrial DNA sequence of ''Scenedesmus obliquus'' reflects an intermediate stage in the evolution of the green algal mitochondrial genome |first1=A.M. |last1=Nedelcu |first2=R.W. |last2=Lee |first3=G. |last3=Lemieux |first4=M.W. |last4=Gray |first5=G. |last5=Burger |pmid=10854413 |pmc=310893 |doi=10.1101/gr.10.6.819 }}</ref> and ''[[Thraustochytrid|Thraustochytrium]]''.<ref>{{Cite journal |last1=Wideman |first1=Jeremy G. |last2=Monier |first2=Adam |last3=Rodríguez-Martínez |first3=Raquel |last4=Leonard |first4=Guy |last5=Cook |first5=Emily |last6=Poirier |first6=Camille |last7=Maguire |first7=Finlay |last8=Milner |first8=David S. |last9=Irwin |first9=Nicholas A. T. |last10=Moore |first10=Karen |last11=Santoro |first11=Alyson E. |date=2019-11-25 |title=Unexpected mitochondrial genome diversity revealed by targeted single-cell genomics of heterotrophic flagellated protists |url=https://www.nature.com/articles/s41564-019-0605-4 |journal=Nature Microbiology |volume=5 |issue=1 |pages=154–165 |doi=10.1038/s41564-019-0605-4 |pmid=31768028 |issn=2058-5276|hdl=10871/39819 |s2cid=208279678 |hdl-access=free }}</ref>

{| class="wikitable" style="border:none; text-align:center;"
|+ Table of alternative stop codons and comparison with the standard genetic code
|-
! rowspan="2" style="width: 250px;" | Genetic code
! rowspan="2" style="width: 25px;" | Translation <br/> table
! colspan="2" | Codon
! rowspan="2" colspan="3" style="width: 200px;" | Translation <br/> with this code
! rowspan="2" style="border:none; width:1px;" |
! rowspan="2" style="width: 50px;" | Standard translation
|-
! style="width: 25px;" | DNA
! style="width: 25px;" | RNA
|-
| rowspan="2" | [[Vertebrate mitochondrial code|Vertebrate mitochondrial]] || rowspan="2" | 2 || <code>AGA</code> || <code>AGA</code> || colspan="3" style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code> || style="border: none; width: 1px;" | || style="background-color:#bbbfe0;" | <code>Arg</code> <code>(R)</code>
|-
| <code>AGG</code> || <code>AGG</code> || colspan="3" style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code> || style="border: none; width: 1px;" | || style="background-color:#bbbfe0;" | <code>Arg</code> <code>(R)</code>
|-
| rowspan="1" | [[Scenedesmus obliquus mitochondrial code|''Scenedesmus obliquus'' mitochondrial]] || rowspan="1" | 22 || |<code>TCA</code> || |<code>UCA</code> || colspan="3" style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code> || style="border: none; width: 1px;" | || style="background-color:#b3dec0;" | <code>Ser</code> <code>(S)</code>
|-
| rowspan="1" | [[Thraustochytrium mitochondrial code|''Thraustochytrium'' mitochondrial]] || rowspan="1" | 23 || <code>TTA</code> || <code>UUA</code> || colspan="3" style="background-color:#B0B0B0;" | <code>STOP = Ter</code> <code>(*)</code> || style="border: none; width: 1px;" | || style="background-color:#ffe75f;" | <code>Leu</code> <code>(L)</code>
|}

{| class="wikitable" style="border:none; text-align:center;"
| style="width: 250px;" | [[Amino acids|Amino-acid]] biochemical properties
| style="background-color:#ffe75f; width: 75px;" | Nonpolar
| style="background-color:#b3dec0; width: 75px;" | Polar
| style="background-color:#bbbfe0; width: 75px;" | Basic
| style="background-color:#f8b7d3; width: 75px;" | Acidic
| style="border: none; width: 1px;" |
| style="background-color:#B0B0B0;" | Termination: stop codon
|}

=== Reassigned stop codons ===
The nuclear genetic code is flexible as illustrated by variant genetic codes that reassign standard stop codons to amino acids.<ref name="Swart2016">{{Cite journal |last1=Swart |first1=Estienne Carl |last2=Serra |first2=Valentina |last3=Petroni |first3=Giulio |last4=Nowacki |first4=Mariusz |year=2016 |title=Genetic Codes with No Dedicated Stop Codon: Context-Dependent Translation Termination |journal=Cell |volume=166 |issue=3 |pages=691–702 |doi=10.1016/j.cell.2016.06.020 |pmc=4967479 |pmid=27426948 }}</ref>

{| class="wikitable" style="border:none; text-align:center;"
|+ Table of conditional stop codons and comparison with the standard genetic code
|-
! rowspan="2" style="width: 250px;" | Genetic code
! rowspan="2" style="width: 25px;" | Translation <br/> table
! colspan="2" | Codon
! rowspan="2" colspan="3" style="width: 200px;" | Conditional <br/> translation
! rowspan="2" style="border:none; width:1px;" |
! rowspan="2" style="width: 50px;" | Standard translation
|-
! style="width: 25px;" | DNA
! style="width: 25px;" | RNA
|-
| rowspan="1" | [[Karyorelict nuclear code|Karyorelict nuclear]] || 27 || <code>TGA</code> || <code>UGA</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#ffe75f;" | <code>Trp</code> <code>(W)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|-
| rowspan="3" | [[Condylostoma nuclear code|''Condylostoma'' nuclear]] || rowspan="3" | 28 || <code>TAA</code> || <code>UAA</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#b3dec0;" | <code>Gln</code> <code>(Q)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|-
| <code>TAG</code> || <code>UAG</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#b3dec0;" | <code>Gln</code> <code>(Q)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|-
| <code>TGA</code> || <code>UGA</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#ffe75f;" | <code>Trp</code> <code>(W)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|-
| rowspan="2" | [[Blastocrithidia nuclear code|''Blastocrithidia'' nuclear]] || rowspan="2" | 31 || <code>TAA</code> || <code>UAA</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#f8b7d3;" | <code>Glu</code> <code>(E)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|-
| <code>TAG</code> || <code>UAG</code> || style="width: 50px; background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code> || style="width: 10px;" | or || style="width: 50px; background-color:#f8b7d3;" |  <code>Glu</code> <code>(E)</code> || style="border: none; width: 1px;" | || style="background-color:#B0B0B0;" | <code>Ter</code> <code>(*)</code>
|}

=== Translation ===
In 1986, convincing evidence was provided that [[selenocysteine]] (Sec) was incorporated co-translationally. Moreover, the codon partially directing its incorporation in the polypeptide chain was identified as UGA also known as the opal termination codon.<ref>{{cite journal |pages=4650–4 |doi=10.1073/pnas.83.13.4650 |title=Nucleotide sequence and expression of the selenocysteine-containing polypeptide of formate dehydrogenase (formate-hydrogen-lyase-linked) from Escherichia coli |year=1986 |last1=Zinoni |first1=F |last2=Birkmann |first2=A |last3=Stadtman |first3=T |last4=Böck |first4=A |journal=Proceedings of the National Academy of Sciences |volume=83 |issue=13 |pmid= 2941757|pmc=323799 |bibcode=1986PNAS...83.4650Z |doi-access=free }}</ref> Different mechanisms for overriding the termination function of this codon have been identified in prokaryotes and in eukaryotes.<ref>{{cite book |last1=Böck |first1=A |title=Encyclopedia of Biological Chemistry |chapter=Selenoprotein Synthesis |year=2013 |pages=210–3 |doi=10.1016/B978-0-12-378630-2.00025-6 |isbn=978-0-12-378631-9 |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780123786302000256 |access-date=23 August 2021}}</ref> A particular difference between these kingdoms is that cis elements seem restricted to the neighborhood of the UAG codon in prokaryotes while in eukaryotes this restriction is not present. Instead such locations seem disfavored albeit not prohibited.<ref>{{cite journal |last1=Mix |first1=H |last2=Lobanov |first2=A |last3=Gladyshev |first3=V |title=SECIS elements in the coding regions of selenoprotein transcripts are functional in higher eukaryotes |journal=Nucleic Acids Research |date=2007 |volume=35 |issue=2 |pages=414–423 |doi=10.1093/nar/gkl1060 |pmid=17169995 |url=https://academic.oup.com/nar/article/35/2/414/2400734|pmc=1802603 }}</ref>

In 2003, a landmark paper described the identification of all known selenoproteins in humans: 25 in total.<ref>{{cite journal |last1=Kryukov |first1=G |last2=Gladyshev |first2=V |title=Characterization of mammalian selenoproteomes |journal=Science |date=2003 |volume=300 |issue=5624 |pages=1439–43 |doi=10.1126/science.1083516 |pmid=12775843 |bibcode=2003Sci...300.1439K |s2cid=10363908 |url=https://www.science.org/doi/full/10.1126/science.1083516|url-access=subscription }}</ref> Similar analyses have been run for other organisms.

The UAG codon can translate into [[pyrrolysine]] (Pyl) in a similar manner.

=== Genomic distribution ===
Distribution of stop codons within the genome of an organism is non-random and can correlate with [[GC-content]].<ref>{{Cite journal|title=Stop codons in bacteria are not selectively equivalent|doi=10.1186/1745-6150-7-30|journal=Biology Direct|pmid=22974057|pmc=3549826|year=2012|volume=7|pages=30|vauthors=Povolotskaya IS, Kondrashov FA, Ledda A, Vlasov PK |doi-access=free }}</ref><ref name="Comprehensive Analysis of Stop Codo">{{cite journal |pages=775–806 |doi=10.1074/jbc.M114.606632 |title=Comprehensive Analysis of Stop Codon Usage in Bacteria and Its Correlation with Release Factor Abundance|year=2014 |last1=Korkmaz|first1=Gürkan |last2=Holm |first2=Mikael |last3=Wiens|first3=Tobias |last4=Sanyal|first4=Suparna |journal=The Journal of Biological Chemistry |volume=289 |issue=44 |pmid=25217634 |pmc=4215218|doi-access=free }}</ref> For example, the ''E. coli'' K-12 genome contains 2705 TAA (63%), 1257 TGA (29%), and 326 TAG (8%) stop codons (GC content 50.8%).<ref>{{cite web |title=''Escherichia coli'' str. K-12 substr. MG1655, complete genome [Genbank Accession Number: U00096] |publisher=NCBI |work=GenBank |url=https://www.ncbi.nlm.nih.gov/nuccore/U00096 |access-date=2013-01-27}}</ref> Also the substrates for the stop codons release factor 1 or release factor 2 are strongly correlated to the abundance of stop codons.<ref name="Comprehensive Analysis of Stop Codo"/> Large scale study of bacteria with a broad range of GC-contents shows that while the frequency of occurrence of TAA is negatively correlated to the GC-content and the frequency of occurrence of TGA is positively correlated to the GC-content, the frequency of occurrence of the TAG stop codon, which is often the minimally used stop codon in a genome, is not influenced by the GC-content.<ref>{{cite journal |pages=6718–25 |doi=10.1128/JB.00682-08 |title= Role of Premature Stop Codons in Bacterial Evolution |year=2008 |last1=Wong|first1=Tit-Yee |last2= Fernandes |first2=Sanjit |last3=Sankhon|first3=Naby |last4=Leong|first4=Patrick P | last5=Kuo|first5=Jimmy |last6=Liu|first6=Jong-Kang |journal=Journal of Bacteriology |volume=190 |issue=20 |pmid=18708500 |pmc=2566208}}</ref>

=== Recognition ===
Recognition of stop codons in bacteria have been associated with the so-called 'tripeptide anticodon',<ref>{{cite journal |doi=10.1038/35001115 |title= A tripeptide 'anticodon' deciphers stop codons in messenger RNA |year=1999 |last1=Ito|first1=Koichi |last2= Uno|first2=Makiko |last3=Nakamura|first3=Yoshikazu |journal=Nature |volume=403 |issue= 6770 |pages= 680–4 |pmid=10688208 |s2cid= 4331695 }}</ref> a highly conserved amino acid motif in RF1 (PxT) and RF2 (SPF). Even though this is supported by structural studies, it was shown that the tripeptide anticodon hypothesis is an oversimplification.<ref>{{cite journal |doi=10.1074/jbc.M117.785238 |title= R213I mutation in release factor 2 (RF2) is one step forward for engineering an omnipotent release factor in bacteria ''Escherichia coli''|year=2017 |last1=Korkmaz|first1=Gürkan |last2= Sanyal|first2=Suparna |journal=Journal of Biological Chemistry|volume=292 |issue= 36|pages= 15134–42|pmid=28743745 |pmc=5592688|doi-access= free}}</ref>

== Nomenclature ==
Stop codons were historically given many different names, as they each corresponded to a distinct class of mutants that all behaved in a similar manner. These mutants were first isolated within [[bacteriophage]]s ([[Enterobacteria phage T4|T4]] and [[Lambda phage|lambda]]), [[virus]]es that infect the bacteria ''[[Escherichia coli]]''. Mutations in viral genes weakened their infectious ability, sometimes creating viruses that were able to infect and grow within only certain varieties of ''E. coli''.

=== ''amber'' mutations ({{mono|UAG}}) ===
{{anchor|Amber mutant}}
They were the first set of [[nonsense mutation]]s to be discovered, isolated by [[Richard H. Epstein]] and [[Charles M. Steinberg|Charles Steinberg]] and named after their friend and graduate Caltech student Harris Bernstein, whose last name means '''"[[amber]]"''' in German (''cf.'' [[:wikt:Bernstein#German|Bernstein]]).<ref>{{cite journal |author=Stahl FW |author-link=Franklin Stahl|year=1995 |title=The amber mutants of phage T4 |journal=Genetics |volume=141 |issue=2 |pages=439–442 |doi=10.1093/genetics/141.2.439 |pmid=8647382 |pmc=1206745}}</ref><ref name="Lewin2011">{{Cite book |last1=Lewin |first1=Benjamin |url=https://books.google.com/books?id=HZ34Ac2bS9sC&pg=PA204 |title=Lewin's Essential GENES |last2=Krebs |first2=Jocelyn E. |last3=Goldstein |first3=Elliott S. |last4=Kilpatrick |first4=Stephen T. |date=2011-04-18 |publisher=Jones & Bartlett |isbn=978-1-4496-4380-5 }}</ref><ref>{{cite journal |vauthors=Edgar B |title=The genome of bacteriophage T4: an archeological dig |journal=Genetics |volume=168 |issue=2 |pages=575–82 |date=October 2004 |pmid=15514035 |pmc=1448817 |doi=10.1093/genetics/168.2.575 }}</ref>

Viruses with amber mutations are characterized by their ability to infect only certain strains of bacteria, known as amber suppressors. These bacteria carry their own mutation that allows a recovery of function in the mutant viruses. For example, a mutation in the tRNA that recognizes the amber stop codon allows translation to "read through" the codon and produce a full-length protein, thereby recovering the normal form of the protein and "suppressing" the amber mutation.<ref>{{cite encyclopedia|url=http://www.bookrags.com/research/amber-ocher-and-opal-mutations-wog/|title=Amber, Ocher, and Opal Mutations Summary|encyclopedia=World of Genetics|author=Robin Cook|publisher=Gale}}</ref>
Thus, amber mutants are an entire class of virus mutants that can grow in bacteria that contain amber suppressor mutations. Similar suppressors are known for ochre and opal stop codons as well.

tRNA molecules carrying unnatural aminoacids have been designed to recognize the amber stop codon in bacterial RNA. This technology allows for incorporation of orthogonal aminoacids (such as p-azidophenylalanine) at specific locations of the target protein.

=== ''ochre'' mutations ({{mono|UAA}}) ===
It was the second stop codon mutation to be discovered. Reminiscent of the usual yellow-orange-brown color associated with amber, this second stop codon was given the name of '''"[[ochre]]"''', an orange-reddish-brown mineral pigment.<ref name="Lewin2011"/>

Ochre mutant viruses had a property similar to amber mutants in that they recovered infectious ability within certain suppressor strains of bacteria. The set of ochre suppressors was distinct from amber suppressors, so ochre mutants were inferred to correspond to a different nucleotide triplet. Through a series of mutation experiments comparing these mutants with each other and other known amino acid codons, [[Sydney Brenner]] concluded that the amber and ochre mutations corresponded to the nucleotide triplets "UAG" and "UAA".<ref name=brenner_1965>{{cite journal |pages=994–8 |doi=10.1038/206994a0 |pmid=5320272 |title=Genetic Code: The 'Nonsense' Triplets for Chain Termination and their Suppression |year=1965 |last1=Brenner |first1=S. |last2=Stretton |first2=A. O. W. |last3=Kaplan |first3=S. |journal=Nature |volume=206 |issue=4988|bibcode=1965Natur.206..994B |s2cid=28502898 }}</ref>

=== ''opal'' or ''umber'' mutations ({{mono|UGA}}) ===
The third and last stop codon in the standard genetic code was discovered soon after, and corresponds to the nucleotide triplet "UGA".<ref>{{cite journal |pages=449–50 |doi=10.1038/213449a0 |title=UGA: A Third Nonsense Triplet in the Genetic Code |year=1967 |last1=Brenner |first1=S. |last2=Barnett |first2=L. |last3=Katz |first3=E. R. |last4=Crick |first4=F. H. C. |journal=Nature |volume=213 |issue=5075 |pmid=6032223|bibcode=1967Natur.213..449B |s2cid=4211867 }}</ref>

To continue matching with the theme of colored minerals, the third nonsense codon came to be known as '''"[[opal]]"''', which is a type of silica showing a variety of colors.<ref name="Lewin2011"/> Nonsense mutations that created this premature stop codon were later called opal mutations or [[umber]] mutations.

== Mutations and disease ==
=== Nonsense ===
[[Nonsense mutations]] are changes in DNA sequence that introduce a premature stop codon, causing any resulting protein to be abnormally shortened. This often causes a loss of function in the protein, as critical parts of the amino acid chain are no longer assembled. Because of this terminology, stop codons have also been referred to as '''nonsense codons'''.

=== Nonstop ===
<!-- Do not edit this subsection title: other pages link here -->
{{anchor|nonstop mutation}}

A '''nonstop mutation''', also called a '''stop-loss variant''', is a [[point mutation]] that occurs within a stop codon. Nonstop mutations cause the continued translation of an [[mRNA]] strand into what should be an untranslated region. Most [[polypeptides]] resulting from a gene with a nonstop mutation lose their function due to their extreme length and the impact on normal folding. Nonstop mutations differ from [[nonsense mutations]] in that they do not create a stop codon but, instead, delete one. Nonstop mutations also differ from [[missense mutation]]s, which are point mutations where a single nucleotide is changed to cause replacement by a different [[amino acid]]. Nonstop mutations have been linked with many inherited diseases including [[endocrine]] disorders,<ref>{{cite journal |title=A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia |author=Pang S. |author2= Wang W. |year=2002 |journal=J Clin Endocrinol Metab |volume=87 |issue=6 |pages=2556–63 |doi=10.1210/jcem.87.6.8559 |pmid=12050213 |display-authors=etal|doi-access=free }}</ref> eye disease,<ref>{{cite journal |author=Doucette, L. |title=A novel, non-stop mutation in ''FOXE3'' causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly |journal=European Journal of Human Genetics |volume=19 |issue=3 |year=2011 |pages=293–9 |doi=10.1038/ejhg.2010.210|display-authors=etal |pmid=21150893 |pmc=3062009}}</ref> and [[neurodevelopmental disorder]]s.<ref>{{cite journal |author=Torres-Torronteras, J. |author2=Rodriguez-Palmero, A. |year=2011 |title=A novel nonstop mutation in TYMP does not induce nonstop mRNA decay in a MNGIE patient with severe neuropathy |journal=Hum. Mutat. |volume=32 |issue=4 |pages=E2061–E2068 |doi=10.1002/humu.21447|display-authors=etal |pmid=21412940|s2cid=24446773 |url=https://hal.archives-ouvertes.fr/hal-00613761/file/PEER_stage2_10.1002%252Fhumu.21447.pdf }}</ref><ref name="STXBP1">{{Cite journal |last1=Spaull |first1=R |last2=Steel |first2=D |last3=Barwick |first3=K |last4=Prabhakar |first4=P |last5=Wakeling |first5=E |last6=Kurian |first6=MA |date=2022-07-23 |title= STXBP1 Stop-Loss Mutation Associated with Complex Early Onset Movement Disorder without Epilepsy |journal=Movement Disorders Clinical Practice |volume=9 |issue=6 |pages=837–840 |doi=10.1002/mdc3.13509 |pmid=35937496 |pmc=9346254 }}</ref>

== Hidden stops ==
[[File:Frameshift deletion (13062713935).jpg|thumb|An example of a single base deletion forming a stop codon.]]
'''Hidden stops''' are non-stop codons that would be read as stop codons if they were [[frameshift]]ed +1 or −1. These prematurely terminate translation if the corresponding frame-shift (such as due to a ribosomal RNA slip) occurs before the hidden stop. It is hypothesised that this decreases resource wastage on nonfunctional proteins and the production of potential [[Cytotoxicity|cytotoxins]]. Researchers at [[Louisiana State University]] propose the ''[[ambush hypothesis]]'', that hidden stops are selected for. Codons that can form hidden stops are used in genomes more frequently compared to synonymous codons that would otherwise code for the same amino acid. Unstable [[Ribosomal RNA|rRNA]] in an organism correlates with a higher frequency of hidden stops.<ref>{{cite journal |pages=701–5 |doi=10.1089/1044549042476910 |title=The Ambush Hypothesis: Hidden Stop Codons Prevent Off-Frame Gene Reading |year=2004 |last1=Seligmann |first1=Hervé |last2=Pollock |first2=David D. |journal=DNA and Cell Biology |volume=23 |issue=10 |pmid=15585128}}</ref>
However, this hypothesis could not be validated with a larger data set.<ref>{{cite journal |pages=1–8 |doi=10.1186/1471-2164-14-418 |title=Ambushing the ambush hypothesis: predicting and evaluating off-frame codon frequencies in Prokaryotic Genomes |year=2013 |last1=Cavalcanti|first1=Andre|last2=Chang |first2=Charlotte H.|last3=Morgens|first3=David W.|journal=BMC Genomics|volume=14 |issue=418 |pmid=23799949 |pmc=3700767 |doi-access=free }}</ref>

Stop-codons and hidden stops together are collectively referred as stop-signals. Researchers at [[University of Memphis]] found that the ratios of the stop-signals on the three reading frames of a genome (referred to as translation stop-signals ratio or TSSR) of genetically related bacteria, despite their great differences in gene contents, are much alike. This nearly identical genomic-TSSR value of genetically related bacteria may suggest that bacterial genome expansion is limited by their unique stop-signals bias of that bacterial species.<ref>{{cite journal |pages= 255–85| doi=10.1080/10590501.2015.1053461 |title=Protein mis-termination initiates genetic diseases, cancers, and restricts bacterial genome expansion |year=2015 |last1=Wong | first1=Tit-Yee|last2=Schwartzbach |first2=Steve|journal=Journal of Environmental Science and Health, Part C |pmid=26087060 |volume=33| issue=3 | bibcode=2015JESHC..33..255W | s2cid=20380447 }}</ref>

== Translational readthrough ==
'''Stop codon suppression'''  or '''translational readthrough''' occurs when in translation a stop codon is interpreted as a sense codon, that is, when a (standard) amino acid is 'encoded' by the stop codon. Mutated [[tRNA]]s can be the cause of readthrough, but also certain [[nucleotide]] motifs close to the stop codon. Translational readthrough is very common in viruses and bacteria, and has also been found as a gene regulatory principle in humans, yeasts, bacteria and drosophila.<ref name="pmid14759362">{{cite journal |vauthors=Namy O, Rousset JP, Napthine S, Brierley I |title=Reprogrammed genetic decoding in cellular gene expression |journal=Molecular Cell |volume=13 |issue=2 |pages=157–68 |year=2004 |pmid=14759362 |doi=10.1016/S1097-2765(04)00031-0
 |doi-access=free }}</ref><ref name="pmid25247702">{{cite journal | vauthors = Schueren F, Lingner T, George R, Hofhuis J, Gartner J, Thoms S | title = Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals | journal = eLife | volume = 3 | pages = e03640 | date = 2014 | pmid = 25247702 | doi = 10.7554/eLife.03640 | pmc=4359377 | doi-access = free }}</ref> This kind of endogenous translational readthrough constitutes a variation of the [[genetic code]], because a stop codon codes for an amino acid. In the case of human [[malate dehydrogenase]], the stop codon is read through with a frequency of about 4%.<ref name="pmid27881739">{{cite journal | vauthors = Hofhuis J, Schueren F, Nötzel C, Lingner T, Gärtner J, Jahn O, Thoms S | title = The functional readthrough extension of malate dehydrogenase reveals a modification of the genetic code | journal = Open Biol | volume = 6 | issue = 11 | pages = 160246 | date = 2016 | pmid = 27881739 | doi = 10.1098/rsob.160246 | pmc=5133446}}</ref> The amino acid inserted at the stop codon depends on the identity of the stop codon itself: Gln, Tyr, and Lys have been found for the UAA and UAG codons, while Cys, Trp, and Arg for the UGA codon have been identified by mass spectrometry.<ref name="pmid25056309">{{cite journal |vauthors=Blanchet S, Cornu D, Argentini M, Namy O |title=New insights into the incorporation of natural suppressor tRNAs at stop codons in ''Saccharomyces cerevisiae''. |journal=Nucleic Acids Res. |volume=42 |issue=15 |pages=10061–72 |year=2014 |pmid=25056309 |doi=10.1093/nar/gku663 |pmc=4150775}}</ref> Extent of readthrough in mammals have widely variable extents, and can broadly diversify the proteome and affect cancer progression.<ref>{{cite journal |last1=Ghosh |first1=Souvik |last2=Guimaraes |first2=Joao C |last3=Lanzafame |first3=Manuela |last4=Schmidt |first4=Alexander |last5=Syed |first5=Afzal Pasha |last6=Dimitriades |first6=Beatrice |last7=Börsch |first7=Anastasiya |last8=Ghosh |first8=Shreemoyee |last9=Mittal |first9=Nitish |last10=Montavon |first10=Thomas |last11=Correia |first11=Ana Luisa |last12=Danner |first12=Johannes |last13=Meister |first13=Gunter |last14=Terracciano |first14=Luigi M |last15=Pfeffer |first15=Sébastien |last16=Piscuoglio |first16=Salvatore |last17=Zavolan |first17=Mihaela |title=Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation |journal=The EMBO Journal |date=15 September 2020 |volume=39 |issue=18 |pages=e103922 |doi=10.15252/embj.2019103922|pmid=32812257 |pmc=7507497 }}</ref>

== Use as a watermark ==
In 2010, when [[Craig Venter]] unveiled the first fully functioning, reproducing cell controlled by [[synthetic biology|synthetic DNA]] he described how his team used frequent stop codons to create [[Mycoplasma laboratorium#Watermarks|watermarks]] in RNA and DNA to help confirm the results were indeed synthetic (and not contaminated or otherwise), using it to encode authors' names and website addresses.<ref>{{cite web |first=Craig |last=Venter |author-link=Craig Venter |url=https://www.ted.com/talks/craig_venter_unveils_synthetic_life?language=en|title=Watch me unveil "synthetic life"|date=21 May 2010 |work=TED Talk}}</ref>

== See also ==
*[[Genetic code]]
*[[Start codon]]
*[[Terminator (genetics)]]
*[[Null-terminated string]]

== References ==
{{reflist|30em}}

[[Category:Molecular genetics]]
[[Category:Gene expression]]
[[Category:Protein biosynthesis]]