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In genetics, a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are typically located near the genes they regulate, on the same strand and upstream (towards the 5' region of the sense strand).

Contents

Overview

In order for the transcription to take place, the enzyme that synthesizes RNA, known as RNA polymerase, must attach to the DNA near a gene. Promoters contain specific DNA sequences and response elements which provide a binding site for RNA polymerase and for proteins called transcription factors that recruit RNA polymerase.

  • In eukaryotes, the process is more complicated, and at least seven different factors are necessary for the binding of an RNA polymerase II to the promoter.

Promoters represent critical elements that can work in concert with other regulatory regions (enhancers, silencers, boundary elements/insulators) to direct the level of transcription of a given gene.

Identification of relative location

As promoters are typically immediately adjacent to the gene in question, positions in the promoter are designated relative to the transcriptional start site, where transcription of RNA begins for a particular gene (i.e., positions upstream are negative numbers counting back from -1, for example -100 is a position 100 base pairs upstream).

Promoter elements

  • Core promoter - the minimal portion of the promoter required to properly initiate transcription
  • Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
  • Distal promoter - the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
    • Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
    • Specific transcription factor binding sites
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Prokaryotic promoters

In prokaryotes, the promoter consists of two short sequences at -10 and -35 positions upstream from the transcription start site. Sigma factors not only help in enhancing RNAP binding to the promoter but helps RNAP target which genes to transcribe.

  • The sequence at -10 is called the Pribnow box, or the -10 element, and usually consists of the six nucleotides TATAAT. The Pribnow box is absolutely essential to start transcription in prokaryotes[citation needed]
  • The other sequence at -35 (the -35 element) usually consists of the seven nucleotides TTGACAT. Its presence allows a very high transcription rate[citation needed].
  • Both of the above consensus sequences, while conserved on average, are not found intact in most promoters. On average only 3 of the 6 base pairs in each consensus sequence is found in any given promoter. No promoter has been identified to date that has intact consensus sequences at both the -10 and -35; it is thought that this would lead to such tight binding by the sigma factor that the polymerase would be unable to initiate productive transcription[citation needed].
  • Some promoters contain a UP element (consensus sequence 5’-AAAWWTWTTTTNNNAAANNN-3'; W = A or T; N = any base) centered at -50; the presence of the -35 element appears to be unimportant for transcription from the UP element-containing promoters.[1]

It should be noted that the above promoter sequences are only recognized by the sigma-70 protein that interacts with the prokaryotic RNA polymerase. Complexes of prokaryotic RNA polymerase with other sigma factors recognize totally different core promoter sequences.

   <-- upstream                                                          downstream -->
5'-XXXXXXXPPPPPXXXXXXPPPPPPXXXXGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGXXXX-3'
           -35       -10       Gene to be transcribed
.
(note that the optimal spacing between the -35 and -10 sequences is 17 nt)

Probability of occurrence of each nucleotide

 for -10 sequence
 T    A    T    A    A    T
77%  76%  60%  61%  56%  82%
 for -35 sequence
 T    T    G    A    C    A
69%  79%  61%  56%  54%  54%

Eukaryotic promoters

Eukaryotic promoters are extremely diverse and are difficult to characterize. They typically lie upstream of the gene and can have regulatory elements several kilobases away from the transcriptional start site(enhancers). In eukaryotes, the transcriptional complex can cause the DNA to bend back on itself, which allows for placement of regulatory sequences far from the actual site of transcription. Many eukaryotic promoters, between 10 and 20% of all genes[2], contain a TATA box (sequence TATAAA), which in turn binds a TATA binding protein which assists in the formation of the RNA polymerase transcriptional complex.[3] The TATA box typically lies very close to the transcriptional start site (often within 50 bases).

Eukaryotic promoter regulatory sequences typically bind proteins called transcription factors which are involved in the formation of the transcriptional complex. An example is the E-box (sequence CACGTG), which binds transcription factors in the basic-helix-loop-helix (bHLH) family (e.g. BMAL1-Clock, cMyc).[4]

Detection of promoters

A wide variety of algorithms have been developed to facilitate detection of promoters in genomic sequence, and promoter prediction is a common element of many gene prediction methods. A promoter region is located before the -35 and -10 Consensus sequences. The closer the promoter region is to the consensus sequences the more often transcription of that gene will take place. There is not a set pattern for promoter regions as there are for consensus sequences.

Evolutionary change

A major question in evolutionary biology is how important tinkering with promoter sequences is to evolutionary change, for example, the changes that have occurred in the human lineage after separating from chimps.

Some evolutionary biologists, for example Allan Wilson, have proposed that evolution in promoter or regulatory regions may be more important than changes in coding sequences over such time frames.

A key reason for the importance of promoters is the potential to incorporate endocrine and environmental[5] signals into changes in gene expression[6]: A great variety of changes in the extracellular or intracellular environment[7] may have impact on gene expression, depending on the exact configuration of a given promoter: the combination and arrangement[8] of specific DNA sequences that constitute the promoter defines the exact groups of proteins that can be bound to the promoter, at a given timepoint[9]. Once the cell receives a physiological, pathological, or pharmacological stimulus, a number of cellular proteins are modified biochemically by signal cascades[10]. By changes in structure, specific proteins acquire the capability to enter the nucleus of the cell and bind to promoter DNA, or to other proteins that themselves are already bound to a given promoter. The multiprotein complexes that are formed have the potential to change levels of gene expression[11]. As a result the gene product may increase or decrease inside the cell.

Binding

The binding of a promoter sequence (P) to a sigma factor-RNAP complex (R) is a two-step process:

  1. R+P ↔ RP(closed). K = 107[citation needed]
  2. RP(closed) → RP(open). K = 10−2[citation needed]

Diseases associated with aberrant promoter function

Though OMIM is a major resource for gathering information on the relationship between mutations and natural variation in gene sequence and susceptibility to hundreds of diseases, it requires a sophisticated search strategy to extract those diseases that are associated with defects in transcriptional control where the promoter is believed to have direct involvement.

This is a list of diseases that evidence suggests have some involvement of promoter malfunction, either through direct mutation of a promoter sequence or mutation in a transcription factor or transcriptional co-activator.

Keep in mind that most diseases are heterogeneous in etiology, meaning that one "disease" is often many different diseases at the molecular level, though the symptoms exhibited and the response to treatment might be identical. How diseases respond differently to treatment as a result of differences in the underlying molecular origins is partially addressed by the discipline of pharmacogenomics.

Not listed here are the many kinds of cancers that involve aberrant changes in transcriptional regulation owing to the creation of chimeric genes through pathological chromosomal translocation. Importantly, intervention on the number or the structure of promoter-bound proteins is a key to treat a disease without to cause a number of changes in the expression of unrelated genes that share particular elements with the specific gene that is the target of therapy[12]. Such genes, whose change is not desirable, are capable to influence the potential of a cell to become cancerous, and form a tumor[13].

Canonical sequences and wild-type

The usage of canonical sequence for a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense.

In the case of a transcription factor binding site, then there may be a single sequence which binds the protein most strongly under specified cellular conditions. This might be called canonical.

However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population, the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions.

Recent evidence also indicates that several genes (including the proto-oncogene c-myc) have G-quadruplex motifs as potential regulatory signals.

Diseases associated with promoter elements

References

  1. ^ Estrem, Gaal, Ross & Gourse (1998) Identification of an UP element consensus sequence for bacterial promoters. PNAS 95:9761-9766.
  2. ^ Gershenzon NI, Ioshikhes IP. Synergy of human Pol II core promoter elements revealed by statistical sequence analysis. Bioinformatics 21 8 1295-300
  3. ^ Smale, T.; Kadonaga, T. (2003). "The RNA polymerase II core promoter". Annual review of biochemistry 72: 449–479. doi:10.1146/annurev.biochem.72.121801.161520. ISSN 0066-4154. PMID 12651739.  edit
  4. ^ Levine, M.; Tjian, R. (Jul 2003). "Transcription regulation and animal diversity". Nature 424 (6945): 147–151. doi:10.1038/nature01763. ISSN 0028-0836. PMID 12853946.  edit
  5. ^ Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc). 2004 Aug;69(8):844-54. Review. PMID: 15377263
  6. ^ Vlahopoulos S, Boldogh I, Casola A, Brasier AR. Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood. 1999 Sep 15;94(6):1878-89. PMID: 10477716
  7. ^ Veitia RA, Nijhout HF. The robustness of the transcriptional response to alterations in morphogenetic gradients. Bioessays. 2006 Mar;28(3):282-9.PMID: 16479586
  8. ^ Tomilin NV. Regulation of mammalian gene expression by retroelements and non-coding tandem repeats. Bioessays. 2008 Apr;30(4):338-48. Review. PMID: 18348251
  9. ^ Celniker SE, Drewell RA. Chromatin looping mediates boundary element promoter interactions. Bioessays. 2007 Jan;29(1):7-10. Review.PMID: 17187351
  10. ^ Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc). 2004 Aug;69(8):844-54. Review.PMID: 15377263
  11. ^ Smith CL. A shifting paradigm: histone deacetylases and transcriptional activation. Bioessays. 2008 Jan;30(1):15-24. Review. PMID: 18081007
  12. ^ Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA. Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? Bioessays. 2009 Jun;31(6):629-41.PMID: 19382224
  13. ^ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V. The role of ATF-2 in oncogenesis.Bioessays. 2008 Apr;30(4):314-27. Review.PMID: 18348191
  14. ^ Hobbs, K; Negri, J; Klinnert, M; Rosenwasser, Lj; Borish, L (1 December 1998). "Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma" (Free full text). American journal of respiratory and critical care medicine 158 (6): 1958–62. ISSN 1073-449X. PMID 9847292. http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=9847292.  edit
  15. ^ Burchard, Eg; Silverman, Ek; Rosenwasser, Lj; Borish, L; Yandava, C; Pillari, A; Weiss, St; Hasday, J; Lilly, Cm; Ford, Jg; Drazen, Jm (1 September 1999). "Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma" (Free full text). American journal of respiratory and critical care medicine 160 (3): 919–22. ISSN 1073-449X. PMID 10471619. http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=10471619.  edit
  16. ^ Kulozik, Ae; Bellan-Koch, A; Bail, S; Kohne, E; Kleihauer, E (May 1991). "Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element". Blood 77 (9): 2054–8. ISSN 0006-4971. PMID 2018842.  edit
  17. ^ Petrij, F.; Giles, H.; Dauwerse, G.; Saris, J.; Hennekam, C.; Masuno, M.; Tommerup, N.; Van Ommen, J. et al. (Jul 1995). "Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP". Nature 376 (6538): 348–351. doi:10.1038/376348a0. ISSN 0028-0836. PMID 7630403.  edit

External links


1911 encyclopedia

Up to date as of January 14, 2010

From LoveToKnow 1911

PROMOTER, one who promotes (Lat. promovere, to move forward), advances or forwards any scheme, project or undertaking. The most general specific sense in which the word is now used is that of a person who takes the steps necessary to the incorporation of a joint-stock company (see Company) or to the passing of a private or local act of parliament. In legal history, a promoter was one who prosecuted offenders, originally as an officer of the Crown, later as a common informer; the term is still used thus of the prosecutor in a suit in an ecclesiastical court.


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