In genetics, a promoter is a DNA sequence that enables a gene to be transcribed. The promoter is recognized by RNA polymerase, which then initiates transcription. In RNA synthesis, promoters are a means to demarcate which genes should be used for messenger RNA creation - and, by extension, control which proteins the cell manufactures.
The perfect promoter is called a canonical sequence.
Promoters represent critical elements that can work in concert with other regulatory regions (enhancers, silencer (DNA), boundary elements/insulators) to direct the level of transcription of a given gene.
The usage of canonical sequence for a promoter is problematic, and should be clarified. 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.
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.
In prokaryotes, the promoter consists of two short sequences at -10 and -35 position upstream of the gene, that is, prior to the gene in the direction of transcription. The sequence at -10 is called the Pribnow box and usually consists of the six nucleotides TATAAT. The Pribnow box is absolutely essential to start transcription in prokaryotes. The other sequence at -35 usually consists of the six nucleotides TTGACA. Its presence allows a very high transcription rate.
<-- upstream downstream --> 5'-XXXXXXXPPPPPXXXXXXPPPPPPXXXXGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGXXXX-3' -35 -10 Gene to be transcribed (note that the optimal spacing between the -35 and -10 sequences is 19 nt)
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 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. 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).
The binding of a promoter sequence (P) to a sigma factor-RNAP complex (R) is a two step process:- R+P <-->RP(closed). K = 10E7
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.- Asthma
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