A promoter is a regulatory region of DNA located upstream (towards the 5' region) of a gene, providing a control point for regulated gene transcription. The structure of part of a DNA double helix Deoxyribonucleic acid, or DNA, is a nucleic acid molecule that contains the genetic instructions used in the development and functioning of all known living organisms. ... Upstream refers to a relative position in DNA or RNA. Each strand of DNA or RNA has a 5 end and a 3 end, so named for the carbons on the deoxyribose ring. ... A diagram of a furanose (sugar-ring) molecule with carbons labelled numerically Directionality, in molecular biology, refers to the end-to-end chemical orientation of a single strand of nucleic acid. ... For a non-technical introduction to the topic, see Introduction to Genetics. ... A micrograph of ongoing gene transcription of ribosomal RNA illustrating the growing primary transcripts. ...

Overview

The promoter contains specific DNA sequences that are recognized by proteins known as transcription factors. These factors bind to the promoter sequences, recruiting RNA polymerase, the enzyme that synthesizes the RNA from the coding region of the gene. In the context of genetics, a transcription factor is a regulatory protein that initiates the transcription of certain genes upon binding with DNA. The binding of a transcription factor to a specific DNA sequence can result in either an increased rate of transcription of the gene, known as activated transcription... This article does not cite any references or sources. ...

• In prokaryotes, the promoter is recognized by RNA polymerase and an associated sigma factor, which in turn are brought to the promoter DNA by an activator protein binding to its own DNA sequence nearby.

• In eukaryotes, the process is more complicated, and at least seven different factors are necessary for the transcription of an RNA polymerase II 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. Prokaryotes are unicellular (in rare cases, multicellular) organisms without a nucleus. ... This article does not cite any references or sources. ... Sigma factor (σ factor) is a prokaryotic initiation factor that binds to RNA polymerase and promotes attachment to promoter sites on DNA. There are seven different sigma factors for different kinds of promoters. ... Kingdoms Eukaryotes are organisms with complex cells, in which the genetic material is organized into membrane-bound nuclei. ... RNA polymerase II (also called RNAP II and Pol II) transcribes DNA to synthesize precursors of mRNA and most snRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. ... In genetics, an enhancer is a short region of DNA that can be bound with proteins (namely, the trans-acting factors, much like a set of transcription factors) to enhance transcription levels of genes (hence the name) in a gene-cluster. ... In genetics a silencer is a DNA sequence capable of binding transcription regulation factors termed repressors. ...

It is worth noting that promoters are not DNA specific, and can in fact locate upstream towards the 3' end of a RNA genome, e.g. Respiratory Syncytial Virus (RSV).

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
  • Transcription Start Site (TSS)
  • Approximately -34
  • A binding site for RNA polymerase
    • RNA polymerase I: transcribes genes encoding ribosomal RNA
    • RNA polymerase II: transcribes genes encoding messenger RNA and certain small nuclear RNAs
    • RNA polymerase III: transcribes genes encoding tRNAs and other small RNAs
  • General transcription factor binding sites
• Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
  • Approximately -250
  • Specific transcription factor binding sites
• 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

This article does not cite any references or sources. ... RNA polymerase I (also called Pol I) transcribes DNA to synthesize rRNA (Ribosomal RNA). ... Ribosomal RNA (rRNA), a type of RNA synthesized in the nucleolus by RNA Pol I, is the central component of the ribosome, the protein manufacturing machinery of all living cells. ... RNA polymerase II (also called RNAP II and Pol II) transcribes DNA to synthesize precursors of mRNA and most snRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. ... The life cycle of an mRNA in a eukaryotic cell. ... RNA polymerase III (also called Pol III) transcribes DNA to synthesize ribosomal 5S rRNA, tRNA and other small RNAs. ... Transfer RNA (abbreviated tRNA) is a small RNA chain (74-93 nucleotides) that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. ...

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. Prokaryotes (pro-KAR-ee-oht) (from Old Greek pro- before + karyon nut or kernel, referring to the cell nucleus, + suffix -otos, pl. ...

• 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.
• The other sequence at -35 (the -35 element) usually consists of the six nucleotides TTGACA. Its presence allows a very high transcription rate.
• Some promoters contain so-called "extended -10 element" (consensus sequence 5’-TGNTATAAT-3'); the presence of the -35 element appears to be unimportant for transcription from the "extended -10" promoters.

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. The Pribnow box (also known as the Pribnow-Schaller box) is the sequence TATAAT of six nucleotides (thymine-adenine-thymine-etc. ... In molecular biology and bioinformatics, a consensus sequence is a way of representing the results of a multiple sequence alignment, where related seqeunces are compared to each other, and similar functional sequence motifs are found. ... A sigma factor (σ factor) is a prokaryotic transcription initiation factor that must be part of RNA polymerase (RNAP) for specific binding to promoter sites on DNA. Different sigma factors are activated in response to different environmental conditions, as are listed below. ...

 <-- 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. 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, but by no means all, 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.^[1] The TATA box typically lies very close to the transcriptional start site (often within 50 bases). Kingdoms Eukaryotes are organisms with complex cells, in which the genetic material is organized into membrane-bound nuclei. ... A TATA box (also called Hogness box) is a DNA sequence (cis-element) found in the promoter region of most genes (it is considered to be a promoter sequence). ... Cartoon of the TATA binding protein structure. ... This article does not cite any references or sources. ...

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).^[2] In the context of genetics, a transcription factor is a regulatory protein that initiates the transcription of certain genes upon binding with DNA. The binding of a transcription factor to a specific DNA sequence can result in either an increased rate of transcription of the gene, known as activated transcription... The introduction to this article provides insufficient context for those unfamiliar with the subject matter. ... Why doesnt this site have bhlh on it? its got really dumb sites but none about bhlh or hlh. ... Bmal (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like) is a gene which encodes proteins regulating circadian rhythm. ... Myc (cMyc) is a protooncogene, which is overexpressed in a wide range of human cancers. ...

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. 7Gene finding typically refers to the area of computational biology that is concerned with algorithmically identifying stretches of sequence, usually genomic DNA, that are biologically functional. ...

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. This article or section does not cite any references or sources. ...

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. Allan Wilson. ...

Binding

The binding of a promoter sequence (P) to a sigma factor-RNAP complex (R) is a two-step process: Sigma factor (σ factor) is a prokaryotic initiation factor that binds to RNA polymerase and promotes attachment to promoter sites on DNA. There are seven different sigma factors for different kinds of promoters. ... The enzyme RNA polymerase or RNAP is a nucleotidyltransferase that polymerises ribonucleotides in accordance with the information present in DNA. RNA polymerase enzymes are essential and are found in all cells of all organisms. ...

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

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. The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... A disease is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. ...

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. A listing of diseases. ... It has been suggested that mutant be merged into this article or section. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ...

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. Pharmacogenomics is the branch of pharmaceutics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drugs efficacy or toxicity. ...

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. Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Chromosomal translocation of the 4th and 20th chromosome. ...

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. An oncogene is a gene that can cause a cell to develop into a tumor cell, possibly resulting in cancer. ... c-Myc is a mammalian transcription factor belonging to the bHLH (basic Helix Loop Helix)_Leucine Zipper family. ... Nucleic acid sequences which are rich in guanine are capable of forming four-stranded structures called G-quadruplexes (Also known as G-tetrads or G4-DNA). ...

Diseases associated with promoter elements

• Asthma^[3][4]
• Beta thalassemia^[5]
• Rubinstein-Taybi syndrome^[6]

Thalassemia (American English) (or Thalassaemia in British English) is an inherited disease of the red blood cells, classified as a hemoglobinopathy. ... Rubinstein-Taybi syndrome (also known as Broad Thumb-Hallux syndrome) is a condition characterized by short stature, moderate to severe mental retardation, distinctive facial features, and broad thumbs and first toes. ...

References

External links

• Directory of computational tools for detecting promoters in sequence data: BioDirectory (Directory). BioDirectory. Oxford Informatics. Retrieved on 2006-12-11.
• ORegAnno - Open Regulatory Annotation Database
• MeSH Promoter Regions (Genetics)

• SwitchDB - An online database used to analyze promoters and transcription start sites (TSSs) throughout the human genome.

• Pleiades Promoter Project - a research project with an aim to generate 160 fully characterized, human DNA promoters of less than 4 kb (MiniPromoters) to drive gene expression in defined brain regions of therapeutic interests.