Editing Operon

{{Short description|Group of open reading frames under the same regulation}}
{{Distinguish|Opteron|Oberon}}
[[File:Operon 1.png|thumb|350px|right|A typical operon]]
In [[genetics]], an '''operon''' is a functioning unit of [[DNA]] containing a cluster of [[gene]]s under the control of a single [[promoter (genetics)|promoter]].<ref>{{cite book | first1 = David E. | last1 = Sadava | first2 = David M. | last2 = Hillis | first3 = H. Craig | last3 = Heller | first4 = May | last4 = Berenbaum | name-list-style = vanc |title=Life: The Science of Biology |publisher=Macmillan|year=2009 |edition=9th |isbn=978-1-4292-1962-4 |page=349 |url=https://books.google.com/books?id=ANT8VB14oBUC&pg=PA349 }}</ref> The genes are [[transcription (biology)|transcribed]] together into an [[Messenger RNA|mRNA]] strand and either [[translation (biology)|translated]] together in the cytoplasm, or undergo [[RNA splicing|splicing]] to create [[Cistron|monocistronic]] mRNAs that are translated separately, i.e. several strands of mRNA that each encode a single gene product. The result of this is that the genes contained in the operon are either [[gene expression|expressed]] together or not at all. Several genes must be ''co-transcribed'' to define an operon.<ref>{{cite book | last1=Lodish | first1=Harvey | last2=Zipursky | first2=Lawrence | last3=Matsudaira | first3=Paul | last4=Baltimore | first4=David | last5=Darnel | first5=James | name-list-style=vanc | title=Molecular Cell Biology | publisher=W. H. Freeman | year=2000 | chapter=Chapter 9: Molecular Definition of a Gene | isbn=978-0-7167-3136-8 | url=https://archive.org/details/molecularcellbio00lodi }}</ref>

Originally, operons were thought to exist solely in [[prokaryote]]s (which includes [[organelle]]s like [[plastid]]s that are derived from [[bacteria]]), but their discovery in [[eukaryote]]s was shown in the early 1990s, and are considered to be rare.<ref name="Kominek">{{cite journal |vauthors=Kominek J, Doering DT, Opulente DA, Shen XX, Zhou X, DeVirgilio J, Hulfachor AB, Groenewald M, Mcgee MA, Karlen SD, Kurtzman CP, Rokas A, Hittinger CT |title=Eukaryotic Acquisition of a Bacterial Operon |journal=Cell |volume=176 |issue=6 |pages=1356–1366.e10 |date=March 2019 |pmid=30799038 |pmc=7295392 |doi=10.1016/j.cell.2019.01.034 |url=}}</ref><ref>{{cite journal | vauthors = Spieth J, Brooke G, Kuersten S, Lea K, Blumenthal T | title = Operons in C. elegans: polycistronic mRNA precursors are processed by trans-splicing of SL2 to downstream coding regions | journal = Cell | volume = 73 | issue = 3 | pages = 521–32 | date = May 1993 | pmid = 8098272 | doi = 10.1016/0092-8674(93)90139-H | s2cid = 26918553 }}</ref><ref>{{cite journal | vauthors = Brogna S, Ashburner M | title = The Adh-related gene of Drosophila melanogaster is expressed as a functional dicistronic messenger RNA: multigenic transcription in higher organisms | journal = The EMBO Journal | volume = 16 | issue = 8 | pages = 2023–31 | date = April 1997 | pmid = 9155028 | pmc = 1169805 | doi = 10.1093/emboj/16.8.2023 }}</ref><ref name="Operons in eukaryotes">{{cite journal | vauthors = Blumenthal T | title = Operons in eukaryotes | journal = Briefings in Functional Genomics & Proteomics | volume = 3 | issue = 3 | pages = 199–211 | date = November 2004 | pmid = 15642184 | doi = 10.1093/bfgp/3.3.199 | doi-access = free }}</ref> In general, expression of prokaryotic operons leads to the generation of [[Cistron|polycistronic]] mRNAs, while eukaryotic operons lead to monocistronic mRNAs.

Operons are also found in viruses such as [[bacteriophage]]s.<ref>{{cite web| title=Definition of Operon| url=http://www.medterms.com/script/main/art.asp?articlekey=32917| work=Medical Dictionary| publisher=MedicineNet.com| access-date=30 December 2012}}</ref><ref name="Liu_2004">{{cite journal | vauthors = Liu J, Mushegian A | title = Displacements of prohead protease genes in the late operons of double-stranded-DNA bacteriophages | journal = Journal of Bacteriology | volume = 186 | issue = 13 | pages = 4369–75 | date = July 2004 | pmid = 15205439 | pmc = 421614 | doi = 10.1128/JB.186.13.4369-4375.2004 }}</ref> For example, [[T7 phage]]s have two operons. The first operon codes for various products, including a special [[T7 RNA polymerase]] which can bind to and transcribe the second operon. The second operon includes a [[lysis]] gene meant to cause the host cell to burst.<ref>{{cite web|title=Bacteriophage Use Operons|url=http://www.dartmouth.edu/~cbbc/courses/bio4/bio4-lectures/ProkGeneControl.html|work=Prokaryotic Gene Control|publisher=Dartmouth College|access-date=30 December 2012|archive-url=https://web.archive.org/web/20130128061441/http://www.dartmouth.edu/~cbbc/courses/bio4/bio4-lectures/ProkGeneControl.html|archive-date=28 January 2013|url-status=dead}}</ref>

== History ==
The term "operon" was first proposed in a short paper in the Proceedings of the [[French Academy of Sciences]] in 1960.<ref name="Jacob1960">{{cite journal | vauthors = Jacob F, Perrin D, Sanchez C, Monod J | title = [Operon: a group of genes with the expression coordinated by an operator] | language = fr | journal = Comptes Rendus Hebdomadaires des Séances de l'Académie des Sciences | volume = 250 | issue = 6 | pages = 1727–9 | date = February 1960 | pmid = 14406329 | url = http://www.weizmann.ac.il/complex/tlusty/courses/landmark/JacobMonod1960.pdf | type = Facsimile version reprinted in 2005 | trans-title = Operon: a group of genes with the expression coordinated by an operator | access-date = 2015-08-27 | archive-url = https://web.archive.org/web/20160304051132/http://www.weizmann.ac.il/complex/tlusty/courses/landmark/JacobMonod1960.pdf | archive-date = 2016-03-04 | url-status = dead }}</ref> From this paper, the so-called general theory of the operon was developed. This theory suggested that in all cases, genes within an operon are negatively controlled by a [[repressor]] acting at a single [[operator (biology)|operator]] located before the first gene. Later, it was discovered that genes could be positively regulated and also regulated at steps that follow transcription initiation. Therefore, it is not possible to talk of a general regulatory mechanism, because different operons have different mechanisms. Today, the operon is simply defined as a cluster of genes transcribed into a single mRNA molecule.  Nevertheless, the development of the concept is considered a landmark event in the history of molecular biology. The first operon to be described was the [[lac operon|''lac'' operon]] in ''[[Escherichia coli|E. coli]]''.<ref name=Jacob1960 />  The 1965 [[Nobel Prize in Physiology and Medicine]] was awarded to [[François Jacob]], [[André Michel Lwoff]] and [[Jacques Monod]] for their discoveries concerning the operon and virus synthesis.

== Overview ==
{{Prokaryote_gene_structure}}
Operons occur primarily in [[prokaryote]]s but also rarely in some [[eukaryote]]s, including [[nematode]]s such as [[Caenorhabditis elegans|''C. elegans'']] and the fruit fly, [[Drosophila|''Drosophila melanogaster'']].<ref name="Kominek"/> [[Ribosomal RNA|rRNA]] genes often exist in operons that have been found in a range of eukaryotes including [[chordate]]s. An operon is made up of several [[structural gene]]s arranged under a common [[promoter (biology)|promoter]] and regulated by a common operator. It is defined as a set of adjacent structural genes, plus the adjacent regulatory signals that affect transcription of the structural genes.<sup>5</sup><ref>{{cite book |vauthors=Miller JH, Suzuki DT, Griffiths AJ, Lewontin RC, Wessler SR, Gelbart WM |title=Introduction to genetic analysis |url=https://archive.org/details/solutionsmanualf0000fixs_u8x1 |url-access=registration |publisher=W.H. Freeman |location=San Francisco |year=2005 |pages=740 |isbn=978-0-7167-4939-4 |edition=8th }}</ref> The regulators of a given operon, including [[repressor]]s, [[Corepressor (genetics)|corepressor]]s, and [[Activator (genetics)|activator]]s, are not necessarily coded for by that operon. The location and condition of the regulators, promoter, operator and structural DNA sequences can determine the effects of common mutations.

Operons are related to [[regulon]]s, [[stimulon]]s and [[modulon]]s; whereas operons contain a set of genes regulated by the same operator, regulons contain a set of genes under regulation by a single regulatory protein, and stimulons contain a set of genes under regulation by a single cell stimulus.  According to its authors, the term "operon" is derived from the verb "to operate".<ref>{{cite journal | vauthors = Jacob F | title = The birth of the operon | journal = Science | volume = 332 | issue = 6031 | pages = 767 | date = May 2011 | pmid = 21566161 | doi = 10.1126/science.1207943 | author-link = François Jacob | bibcode = 2011Sci...332..767J | doi-access = free }}</ref>

== As a unit of transcription ==

An operon contains one or more [[structural gene]]s which are generally transcribed into one [[polycistronic]] [[mRNA]] (a single mRNA molecule that codes for more than one [[protein]]). However, the definition of an operon does not require the mRNA to be polycistronic, though in practice, it usually is.<ref name="Operons in eukaryotes"/> Upstream of the structural genes lies a [[promoter (biology)|promoter]] sequence which provides a site for [[RNA polymerase]] to bind and initiate transcription. Close to the promoter lies a section of DNA called an ''operator''.

== Operons versus clustering of prokaryotic genes  ==
All the [[structural gene]]s of an operon are turned ON or OFF together, due to a single promoter and operator upstream to them, but sometimes more control over the gene expression is needed. To achieve this aspect, some bacterial genes are located near together, but there is a specific promoter for each of them; this is called [[Metabolic gene cluster|gene clustering]]. Usually these genes encode proteins which will work together in the same pathway, such as a metabolic pathway. Gene clustering helps a prokaryotic cell to produce metabolic enzymes in a correct order.<ref>{{cite journal | vauthors = Lee JM, Sonnhammer EL | title = Genomic gene clustering analysis of pathways in eukaryotes | journal = Genome Research | volume = 13 | issue = 5 | pages = 875–82 | date = May 2003 | pmid = 12695325 | pmc = 430880 | doi = 10.1101/gr.737703 }}</ref>
In one study, it has been posited that in the [[Asgard (archaea)]], ribosomal protein coding genes occur in clusters that are less conserved in their organization than in other [[Archaea]]; the closer an [[Asgard (archaea)]] is to the [[eukaryote]]s, the more dispersed is the arrangement of the ribosomal protein coding genes.<ref>{{cite journal | vauthors = Tirumalai MR, Sivaraman RV, Kutty LA, Song EL, Fox GE | title = Ribosomal Protein Cluster Organization in Asgard Archaea | journal = Archaea | volume = 2023 |date = September 2003 | pages = 1–16 | doi = 10.1155/2023/5512414 | doi-access = free | pmid = 38314098 | pmc = 10833476 }}</ref>

== General structure ==
{{anchor|General structure}}<!--anchor for redirect in case of header name change-->
[[File:Lac Operon.svg|thumb|300px|'''''1'': RNA Polymerase, ''2'': Repressor, ''3'': Promoter, ''4'': Operator, ''5'': Lactose, ''6'': lacZ, ''7'': lacY, ''8'': lacA.
''' '''Top''': The gene is essentially turned off. There is no lactose to inhibit the repressor, so the repressor binds to the operator, which obstructs the RNA polymerase from binding to the promoter and making lactase. 
'''Bottom''': The gene is turned on. Lactose is inhibiting the repressor, allowing the RNA polymerase to bind with the promoter, and express the genes, which synthesize lactase. Eventually, the lactase will digest all of the lactose, until there is none to bind to the repressor. The repressor will then bind to the operator, stopping the manufacture of lactase.]]

An operon is made up of 3 basic DNA components:

* [[promoter (biology)|Promoter]] – a [[nucleotide]] sequence that enables a gene to be [[transcription (genetics)|transcribed]]. The promoter is recognized by [[RNA polymerase]], which then initiates transcription.  In RNA synthesis, promoters indicate which genes should be used for messenger RNA creation – and, by extension, control which proteins the cell produces.
*{{anchor|Operator}} '''Operator''' – a segment of [[DNA]] to which a [[repressor]] binds.  It is classically defined in the [[lac operon]] as a segment between the promoter and the genes of the operon.<ref name=blewin>{{cite book |last=Lewin |first=Benjamin |name-list-style=vanc |title=Genes IV |publisher=Oxford University Press |location=Oxford |year=1990 |pages=[https://archive.org/details/genesiv00lewi/page/243 243–58] |isbn=978-0-19-854267-4 |edition=4th |url=https://archive.org/details/genesiv00lewi/page/243 }}</ref> The main operator (O1) in the ''lac'' operon is located slightly downstream of the promoter; two additional operators, O2 and O3 are located at -82 and +412, respectively.  In the case of a repressor, the repressor protein physically obstructs the RNA polymerase from transcribing the genes.
* [[Structural gene]]s – the genes that are co-regulated by the operon.

Not always included within the operon, but important in its function is a [[regulatory gene]], a constantly expressed gene which codes for [[repressor proteins]]. The regulatory gene does not need to be in, adjacent to, or even near the operon to control it.<ref>{{cite book |last=Mayer |first=Gene | name-list-style = vanc | chapter = Bacteriology – Chapter Nine Genetic Regulatory Mechanisms| chapter-url = http://pathmicro.med.sc.edu/mayer/geneticreg.htm|title=Microbiology and Immunology Online|publisher=University of South Carolina School of Medicine|access-date=30 December 2012}}</ref>

An [[inducer]] (small molecule) can displace a repressor (protein) from the operator site (DNA), resulting in an uninhibited operon.

Alternatively, a [[corepressor]] can bind to the repressor to allow its binding to the operator site.  A good example of this type of regulation is seen for the [[trp operon]].

== Regulation ==

Control of an operon is a type of [[gene regulation]] that enables organisms to regulate the expression of various genes depending on environmental conditions. Operon regulation can be either negative or positive by induction or repression.<ref name=blewin/>

Negative control involves the binding of a [[repressor]] to the operator to prevent transcription.

* In ''negative inducible operons'', a regulatory repressor protein is normally bound to the operator, which prevents the transcription of the genes on the operon. If an [[inducer]] molecule is present, it binds to the repressor and changes its conformation so that it is unable to bind to the operator. This allows for expression of the operon. The [[lac operon|''lac'' operon]] is a negatively controlled inducible operon, where the inducer molecule is [[allolactose]].
* In ''negative repressible operons'', transcription of the operon normally takes place. Repressor proteins are produced by a [[regulator gene]], but they are unable to bind to the operator in their normal conformation. However, certain molecules called corepressors are bound by the repressor protein, causing a conformational change to the active site. The activated repressor protein binds to the operator and prevents transcription. The [[Trp operon|''trp'' operon]], involved in the synthesis of [[tryptophan]] (which itself acts as the corepressor), is a negatively controlled repressible operon.

Operons can also be positively controlled. With positive control, an [[Activator (genetics)|activator]] protein stimulates transcription by binding to DNA (usually at a site other than the operator).

* In ''positive inducible operons'', activator proteins are normally unable to bind to the pertinent DNA. When an [[inducer]] is bound by the activator protein, it undergoes a change in conformation so that it can bind to the DNA and activate transcription. Examples of positive inducible operons include the MerR family of transcriptional activators. 
* In ''positive repressible operons'', the activator proteins are normally bound to the pertinent DNA segment. However, when an [[Reaction inhibitor|inhibitor]] is bound by the activator, it is prevented from binding the DNA. This stops activation and transcription of the system.

== The ''lac'' operon ==

{{Main|lac operon}}

The ''lac'' operon of the [[model organism|model]] bacterium ''[[Escherichia coli]]'' was the first operon to be discovered and provides a typical example of operon function. It consists of three adjacent [[structural gene]]s, a [[promoter (biology)|promoter]], a [[Terminator (genetics)|terminator]], and an [[operator (biology)|operator]]. The ''lac'' operon is regulated by several factors including the availability of [[glucose]] and [[lactose]]. It can be activated by [[allolactose]]. Lactose binds to the repressor protein and prevents it from repressing gene transcription. This is an example of the [[derepression|derepressible]] (from above: negative inducible) model. So it is a negative inducible operon induced by presence of lactose or allolactose.

== The ''trp'' operon ==

{{Main|trp operon}}
[[File:Trp operon organization across three different bacterial species.png|thumb|Arrangement of genes within the trp operon of three  bacterial genomes.]]
Discovered in 1953 by [[Jacques Monod]] and colleagues, the trp operon in ''E. coli'' was the first repressible operon to be discovered.  While the lac operon can be activated by a chemical ([[allolactose]]), the tryptophan (Trp) operon is inhibited by a chemical (tryptophan).  This operon contains five structural genes: trp E, trp D, trp C, trp B, and trp A, which encodes [[tryptophan synthetase]].  It also contains a promoter which binds to RNA polymerase and an operator which blocks transcription when bound to the protein synthesized by the repressor gene (trp R) that binds to the operator.  In the lac operon, lactose binds to the repressor protein and prevents it from repressing gene transcription, while in the trp operon, tryptophan binds to the repressor protein and enables it to repress gene transcription.  Also unlike the lac operon, the trp operon contains a leader peptide and an [[attenuator (genetics)|attenuator]] sequence which allows for graded regulation.<ref>{{cite book |vauthors=Cummings MS, Klug WS |title=Concepts of genetics |publisher=Pearson Education |location=Upper Saddle River, NJ |year=2006 |pages=394–402 |isbn=978-0-13-191833-7 |edition=8th}}</ref> This is an example of the [[corepressor (genetics)|corepressible]] model.

== Predicting the number and organization of operons ==

The number and organization of operons has been studied most critically in ''[[Escherichia coli|E. coli]]''. As a result, predictions can be made based on an organism's genomic sequence.

One prediction method uses the intergenic distance between reading frames as a primary predictor of the number of operons in the genome. The separation merely changes the frame and guarantees that the read through is efficient. Longer stretches exist where operons start and stop, often up to 40–50 bases.<ref>{{cite journal | vauthors = Salgado H, Moreno-Hagelsieb G, Smith TF, Collado-Vides J | title = Operons in Escherichia coli: genomic analyses and predictions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 12 | pages = 6652–7 | date = June 2000 | pmid = 10823905 | pmc = 18690 | doi = 10.1073/pnas.110147297 | bibcode = 2000PNAS...97.6652S | doi-access = free }}</ref>

An alternative method to predict operons is based on finding gene clusters where gene order and orientation is conserved in two or more genomes.<ref>{{cite journal | vauthors = Ermolaeva MD, White O, Salzberg SL | title = Prediction of operons in microbial genomes | journal = Nucleic Acids Research | volume = 29 | issue = 5 | pages = 1216–21 | date = March 2001 | pmid = 11222772 | pmc = 29727 | doi = 10.1093/nar/29.5.1216 }}</ref>

Operon prediction is even more accurate if the functional class of the molecules is considered. Bacteria have clustered their reading frames into units, sequestered by co-involvement in protein complexes, common pathways, or shared substrates and transporters. Thus, accurate prediction would involve all of these data, a difficult task indeed.

[[Pascale Cossart]]'s laboratory was the first to experimentally identify all operons of a microorganism, ''[[Listeria monocytogenes]]''.  The 517 polycistronic operons are listed in a 2009 study describing the global changes in transcription that occur in ''L. monocytogenes'' under different conditions.<ref>{{cite journal | vauthors = Toledo-Arana A, Dussurget O, Nikitas G, Sesto N, Guet-Revillet H, Balestrino D, Loh E, Gripenland J, Tiensuu T, Vaitkevicius K, Barthelemy M, Vergassola M, Nahori MA, Soubigou G, Régnault B, Coppée JY, Lecuit M, Johansson J, Cossart P | title = The Listeria transcriptional landscape from saprophytism to virulence | journal = Nature | volume = 459 | issue = 7249 | pages = 950–6 | date = June 2009 | pmid = 19448609 | doi = 10.1038/nature08080 | bibcode = 2009Natur.459..950T | s2cid = 4341657 }}</ref>

== Operons response to genome-wide stresses ==
Primary promoters are the main controllers of operons. However, many operons have internal promoters. For example, half of all operons of ''[[Escherichia coli|E. coli]]'' have internal promoters''.'' What happens when both the primary as well as the internal promoters are simultaneously perturbed? A recent study followed how each gene in each operon responded to such genome-wide stresses.<ref>{{Cite journal |last=Jagadeesan |first=Rahul |last2=Dash |first2=Suchintak |last3=Palma |first3=Cristina S. D. |last4=Baptista |first4=Ines S. C. |last5=Chauhan |first5=Vatsala |last6=Mäkelä |first6=Jarno |last7=Ribeiro |first7=Andre S. |date=2025-05-16 |title=Dynamics of bacterial operons during genome-wide stresses is influenced by premature terminations and internal promoters |url=https://www.science.org/doi/10.1126/sciadv.adl3570 |journal=Science Advances |language=en |volume=11 |issue=20 |doi=10.1126/sciadv.adl3570 |issn=2375-2548 |pmc=12083536 |pmid=40378216}}</ref> They found that many transcription events of operons end prematurely in those conditions. They also found that internal promoters compensate significantly for those terminations creating a wave-like response pattern along operons. Next, it was shown that the same occurs in evolutionarily distant bacteria, such as Bacillus subtilis, Corynebacterium glutamicum, and Helicobacter pylori.

== See also ==
{{Portal|Evolutionary biology|Biology|}}
* [[Evolutionary developmental biology]]
* [[Genetic code]]
* [[Gene regulatory network]]
* [[L-arabinose operon]]
* [[Protein biosynthesis]]
* [[TATA box]]
* [[Umu Chromotest]]

== References ==
{{Reflist}}

== External links ==
* [https://archive.today/20121214195153/http://www.broad.mit.edu/annotation/tbdb/operon/ ''Mycobacterium tuberculosis'' H37Rv Operon Correlation Browser]
* [http://operondb.jp OBD] - [[Operon database]] (a bit awkward to use though)
{{Transcription}}
{{Regulation of gene expression}}
{{genarch}}
{{Authority control}}

[[Category:Gene expression]]
[[Category:Operons|*]]