Operon

A typical operon

In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter.^[1][2] The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create 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 expressed together or not at all. Several genes must be both co-transcribed and co-regulated to define an operon.^[3]

Originally, operons were thought to exist solely in prokaryotes, but since the discovery of the first operons in eukaryotes in the early 1990s,^[4][5] more evidence has arisen to suggest they are more common than previously assumed.^[6]

History

The term "operon" was first proposed in a short paper in the Proceedings of the French Academy of Science in 1960 ^[7]. From this paper, the so-called general theory of the operon was developed. This theory suggested that all genes are controlled by means of operons through a single feedback regulatory mechanism– repression. Later, it was discovered that the regulation of genes is a much more complicated process. Indeed, it is not possible to talk of a general regulatory mechanism, because different operons have different mechanisms. Despite modifications, 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 in E. coli.^[2] 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

Operons occur primarily in prokaryotes but also in some eukaryotes, including nematodes such as C. elegans. , and Drosophila melanogaster flies. rRNA genes often exist in operons that have been found in a range of eukaryotes including chordates. An operon is made up of several structural genes arranged under a common 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.^5[8] The regulators of a given operon, including repressors, corepressors, and activators, 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 regulons, stimulons and modulons; 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" means "to operate"^[9].

As a unit of transcription

An operon contains one or more structural genes 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^[10] . Upstream of the structural genes lies a 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. The operon may also contain regulatory genes such as a repressor gene, which codes for a regulatory protein that binds to the operator and inhibits transcription. Regulatory genes need not be part of the operon itself, but may be located elsewhere in the genome. The repressor molecule will reach the operator to block the transcription of the structural genes.^{[citation needed]}

Structure

This is the general structure of an operon:

• Promoter – a nucleotide sequence that enables a gene to be 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 manufactures.
• Operator – a segment of DNA that a regulator binds to. It is classically defined in the lac operon as a segment between the promoter and the genes of the operon.^[11] In the case of a repressor, the repressor protein physically obstructs the RNA polymerase from transcribing the genes.
• Structural genes – the genes that are co-regulated by the 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.^[11]

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.

• 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 state. The activated repressor protein binds to the operator and prevents transcription.

Operons can also be positively controlled. With positive control, an 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.

• In positive repressible operons, the activator proteins are normally bound to the pertinent DNA segment. However, when a corepressor is bound by the activator, it is prevented from binding the DNA. This stops activation and transcription of the system.

The lac operon

Main article: lac operon

The lac operon of the 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 genes, a promoter, a terminator, and an operator. The lac operon is regulated by several factors including the availability of glucose and lactose. This is an example of the derepressible (from above: negative inducible) model.

The trp operon

Main article: trp operon

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 sequence which allows for graded regulation.^[12] This is an example of the corepressible model.

Predicting the number and organization of operons

The number and organization of operons has been studied most critically in 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.^[13]

An alternative method to predict operons is based on finding gene clusters where gene order and orientation is conserved in two or more genomes.^[14]

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 published in 2009 the first full map of an operon, identifying the genetic switches that operate in Listeria under different conditions.^[15]

See also

• gene regulatory network
• TATA box
• L-arabinose operon
• Protein biosynthesis
• Genetic code

References

1. ^ Sadava, David et al. (2009). Life: The Science of Biology (9th ed.). Macmillan. p. 349. ISBN 9781429219624. http://books.google.com/books?id=ANT8VB14oBUC&pg=PA349. 
2. ^ ^{a b} Jacob, F.; Perrin, D.; Sanchez, C.; Monod, J. (Feb 1960). "Operon: a group of genes with the expression coordinated by an operator". Comptes rendus hebdomadaires des seances de l'Academie des sciences 250 (6): 1727–1729. doi:10.1016/j.crvi.2005.04.005. ISSN 0001-4036. PMID 14406329. http://www.weizmann.ac.il/complex/tlusty/courses/landmark/JacobMonod1960.pdf.  edit
3. ^ Lodish, Harvey; Zipursky, Lawrence; Matsudaira, Paul; Baltimore, David; Darnel, James (2000). "Chapter 9: Molecular Definition of a Gene". Molecular Cell Biology. W. H. Freeman. ISBN 0-7167-3136-2. 
4. ^ Spieth, J.; Brooke, G.; Kuersten, S.; Lea, K.; Blumenthal, T. (1993). "Operons in C. Elegans: polycistronic mRNA precursors are processed by trans-splicing of SL2 to downstream coding regions". Cell 73 (3): 521–532. doi:10.1016/0092-8674(93)90139-H. PMID 8098272.  edit
5. ^ Brogna, S.; Ashburner, M. (1997). "The Adh-related gene of Drosophila melanogaster is expressed as a functional dicistronic messenger RNA: Multigenic transcription in higher organisms". The EMBO Journal 16 (8): 2023–2031. doi:10.1093/emboj/16.8.2023. PMC 1169805. PMID 9155028. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1169805.  edit
6. ^ Blumenthal, T. (2004). "Operons in eukaryotes". Briefings in Functional Genomics and Proteomics 3 (3): 199–211. doi:10.1093/bfgp/3.3.199. PMID 15642184.  edit
7. ^ Jacob, F.; Perrin, D.; Sanchez, C.; Monod, J. (Feb 1960). "Operon: a group of genes with the expression coordinated by an operator". Comptes rendus hebdomadaires des seances de l'Academie des sciences 250 (6): 1727–1729. doi:10.1016/j.crvi.2005.04.005. ISSN 0001-4036. PMID 14406329. http://www.weizmann.ac.il/complex/tlusty/courses/landmark/JacobMonod1960.pdf.  edit
8. ^ Miller JH, Suzuki DT, Griffiths AJF, Lewontin RC, Wessler SR, Gelbart WM (2005). Introduction to genetic analysis (8th ed.). San Francisco: W.H. Freeman. pp. 740. ISBN 0-7167-4939-4. 
9. ^ Jacob, F.�o. (2011). "The Birth of the Operon". Science 332 (6031): 767–767. doi:10.1126/science.1207943.  edit
10. ^ Blumenthal, Thomas (2004). "Operons in Eukaryotes". Brief Funct Genomic Proteomic, 3 (3): 199-211. 
11. ^ ^{a b} Lewin, Benjamin (1990). Genes IV (4th ed.). Oxford [Oxfordshire]: Oxford University Press. pp. 243–58. ISBN 0-19-854267-4. 
12. ^ Cummings MS, Klug WS (2006). Concepts of genetics (8th ed.). Upper Saddle River, NJ: Pearson Education. pp. 394–402. ISBN 0-13-191833-8. 
13. ^ Salgado, H.; Moreno-Hagelsieb, G.; Smith, T.; Collado-Vides, J. (2000). "Operons in Escherichia coli: Genomic analyses and predictions". Proceedings of the National Academy of Sciences 97 (12): 6652–6657. doi:10.1073/pnas.110147297. PMC 18690. PMID 10823905. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18690.  edit
14. ^ Ermolaeva, M.; White, O.; Salzberg, S. (2001). "Prediction of operons in microbial genomes". Nucleic Acids Research 29 (5): 1216–1221. doi:10.1093/nar/29.5.1216. PMC 29727. PMID 11222772. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=29727.  edit
15. ^ Toledo-Arana, A.; Dussurget, O.; Nikitas, G.; Sesto, N.; Guet-Revillet, H.; Balestrino, D.; Loh, E.; Gripenland, J. et al. (2009). "The Listeria transcriptional landscape from saprophytism to virulence". Nature 459 (7249): 950–956. doi:10.1038/nature08080. PMID 19448609.  edit

External links

• Mycobacterium tuberculosis H37Rv Operon Correlation Browser
• The Operon Concept: F.Jacob & J.Monad-1961