Editing TATA box

{{Short description|DNA sequence}}
[[File:TATA_box_description.png|thumb|515x515px|'''Figure 1.''' TATA box structural elements. The TATA box consensus sequence is TATAWAW, where W is either A or T.]]
In [[molecular biology]], the '''TATA box''' (also called the '''Goldberg&ndash;Hogness box''')<ref name=":0">{{cite journal | vauthors = Lifton RP, Goldberg ML, Karp RW, Hogness DS | title = The organization of the histone genes in Drosophila melanogaster: functional and evolutionary implications | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 42 | pages = 1047–51 | date = 1978 | pmid = 98262 | doi = 10.1101/sqb.1978.042.01.105 | issue=2}}</ref> is a [[DNA sequence|sequence]] of [[DNA]] found in the [[Promoter (genetics)|core promoter region]] of [[gene]]s in [[archaea]] and [[eukaryote]]s.<ref name=":11">{{cite journal | vauthors = Smale ST, Kadonaga JT | title = The RNA polymerase II core promoter | journal = Annual Review of Biochemistry | volume = 72 | pages = 449–79 | date = 2003 | pmid = 12651739 | doi = 10.1146/annurev.biochem.72.121801.161520 }}</ref> The [[bacteria]]l [[Homology (biology)|homolog]] of the TATA box is called the [[Pribnow box]] which has a shorter [[consensus sequence]].

The TATA box is considered a [[Noncoding DNA|non-coding DNA]] [[Nucleic acid sequence|sequence]] (also known as a [[cis-regulatory element]]). It was termed the "TATA box" as it contains a consensus sequence characterized by repeating T and A [[base pair]]s.<ref name=":4" /> How the term "box" originated is unclear. In the 1980s, while investigating [[Nucleic acid sequence|nucleotide sequences]] in [[mouse]] [[genome]] [[Locus (genetics)|loci]], the Hogness box sequence was found and "boxed in" at the -31 position.<ref name=":18">{{cite journal | vauthors = Ohshima Y, Okada N, Tani T, Itoh Y, Itoh M | title = Nucleotide sequences of mouse genomic loci including a gene or pseudogene for U6 (4.8S) nuclear RNA | journal = Nucleic Acids Research | volume = 9 | issue = 19 | pages = 5145–58 | date = October 1981 | pmid = 6171774 | doi = 10.1093/nar/9.19.5145 | pmc=327505}}</ref> When [[Consensus sequence|consensus]] [[nucleotide]]s and alternative ones were compared, homologous regions were "boxed" by the researchers.<ref name=":18" /> The boxing in of sequences sheds light on the origin of the term "box".

The TATA box was first identified in 1978<ref name=":0" />  as a component of eukaryotic promoters. [[Transcription (biology)|Transcription]] is initiated at the TATA box in TATA-containing genes. The TATA box is the binding site of the [[TATA-binding protein]] (TBP) and other [[transcription factor]]s in some eukaryotic genes. Gene transcription by RNA polymerase II depends on the regulation of the core promoter by long-range regulatory elements such as enhancers and silencers.<ref name=":16" /> Without proper regulation of transcription, eukaryotic organisms would not be able to properly respond to their environment.

Based on the sequence and mechanism of TATA box initiation, [[mutation]]s such as [[Insertion (genetics)|insertions]], [[Deletion (genetics)|deletions]], and [[point mutation]]s to this [[consensus sequence]] can result in [[Phenotype|phenotypic]] changes. These phenotypic changes can then turn into a [[disease]] phenotype. Some diseases associated with [[mutation]]s in the TATA box include [[Stomach cancer|gastric cancer]], [[spinocerebellar ataxia]], [[Huntington's disease]], [[Visual impairment|blindness]], [[Thalassemia|β-thalassemia]], [[immunosuppression]], [[Gilbert's syndrome]], and [[Subtypes of HIV|HIV-1]]. The TATA-binding protein (TBP) could also be targeted by [[virus]]es as a means of viral transcription.<ref>{{cite journal | vauthors = Mainz D, Quadt I, Stranzenbach AK, Voss D, Guarino LA, Knebel-Mörsdorf D | title = Expression and nuclear localization of the TATA-box-binding protein during baculovirus infection | journal = The Journal of General Virology | volume = 95 | issue = Pt 6 | pages = 1396–407 | date = June 2014 | pmid = 24676420 | doi = 10.1099/vir.0.059949-0 | s2cid = 33480957 | doi-access = free }}</ref>

== History ==

=== Discovery ===
The TATA box was the first eukaryotic core promoter motif to be identified in 1978 by American biochemist [[David Hogness]]<ref name=":0" /> while he and his graduate student, Michael Goldberg were on sabbatical at the [[University of Basel]] in Switzerland.<ref>{{Cite book|title=Master Control Genes in Development and Evolution: The Homeobox Story|url=https://archive.org/details/mastercontrolgen0000gehr|url-access=registration|last=Gehring|first=Walter J. | name-list-style = vanc |publisher=Yale University Press|year=1998|isbn=978-0300074093|location=New Haven}}</ref> They first discovered the TATA sequence while analyzing 5' [[DNA]] [[Promoter (genetics)|promoter]] sequences in ''[[Drosophila]],'' [[mammal]]ian, and [[Virus|viral]] genes.<ref name=":14">{{cite journal | vauthors = Kutach AK, Kadonaga JT | title = The downstream promoter element DPE appears to be as widely used as the TATA box in Drosophila core promoters | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4754–64 | date = July 2000 | pmid = 10848601 | pmc = 85905 | doi=10.1128/mcb.20.13.4754-4764.2000}}</ref><ref name=":11" /> The TATA box was found in [[protein]] coding [[gene]]s transcribed by [[RNA polymerase II]].<ref name=":11" />

=== Evolutionary history ===
Most research on the TATA box has been conducted on yeast, human, and ''Drosophila'' genomes, however, similar elements have been found in [[archaea]] and ancient [[eukaryote]]s.<ref name=":11" /> In archaea species, the promoter contains an 8 bp AT-rich sequence located ~24 bp upstream of the transcription start site. This sequence was originally called Box A, which is now known to be the sequence that interacts with the homologue of the archaeal [[TATA-binding protein]] (TBP). Also, even though some studies have uncovered several similarities, there are others that have detected notable differences between archaeal and eukaryotic TBP. The archaea protein exhibits a greater symmetry in its primary sequence and in the distribution of [[Electrostatics|electrostatic]] charge, which is important because the higher symmetry lowers the protein's ability to bind the TATA box in a polar manner.<ref name=":11" />

Even though the TATA box is present in many eukaryotic promoters, it is not contained in the majority of promoters. One study found less than 30% of 1031 potential promoter regions contain a putative TATA box motif in humans.<ref>{{cite journal | vauthors = Suzuki Y, Tsunoda T, Sese J, Taira H, Mizushima-Sugano J, Hata H, Ota T, Isogai T, Tanaka T, Nakamura Y, Suyama A, Sakaki Y, Morishita S, Okubo K, Sugano S | title = Identification and characterization of the potential promoter regions of 1031 kinds of human genes | journal = Genome Research | volume = 11 | issue = 5 | pages = 677–84 | date = May 2001 | pmid = 11337467 | pmc = 311086 | doi =  10.1101/gr.gr-1640r}}</ref> In ''Drosophila,'' less than 40% of 205 core promoters contain a TATA box.<ref name=":14" /> When there is an absence of the TATA box and TBP is not present, the [[downstream promoter element]] (DPE) in cooperation with the [[initiator element]] (Inr) bind to the transcription factor II D ([[TFIID]]), initiating transcription in TATA-less promoters. The DPE has been identified in three ''Drosophila'' TATA-less promoters and in the TATA-less human [[IRF1|IRF-1]] promoter.<ref name=":12">{{cite book|title=Cellular and Biochemical Science|last=Tripathi|first=G.|publisher=I.K. International Publishing House Pvt. Ltd|year=2010|isbn=9788188237852|location=New Delhi|pages=373–374}}</ref>

== Features ==

=== Location ===
Promoter sequences vary between [[bacteria]] and [[eukaryote]]s.&nbsp;In eukaryotes, the TATA box is located 25 [[base pair]]s [[Upstream and downstream (DNA)|upstream]] of the start site that [[RPA4|Rpb4]]/Rbp7 use to initiate [[Transcription (biology)|transcription]]. In [[metazoans]], the TATA box is located 30 base pairs upstream of the transcription start site.<ref name=":16" /> While in yeast, ''[[Saccharomyces cerevisiae|S. cerevisiae]]'', the TATA box has a variable position which can range from 40 to 100 bp upstream of the start site. The TATA box is also found in 40% of the [[Promoter (genetics)|core promoters]] of genes that code for the [[Actin|actin cytoskeleton]] and [[Contractile ring|contractile]] apparatus in cells.<ref name=":16" />

The type of core promoter affects the level of transcription and expression of a [[gene]]. [[TATA-binding protein|TATA-binding protein (TBP)]] can be recruited in two ways, by SAGA, a cofactor for [[RNA polymerase II]], or by [[TFIID]].<ref name=":17">{{cite journal | vauthors = Baptista T, Grünberg S, Minoungou N, Koster MJ, Timmers HT, Hahn S, Devys D, Tora L | title = SAGA Is a General Cofactor for RNA Polymerase II Transcription | journal = Molecular Cell | volume = 68 | issue = 1 | pages = 130–143.e5 | date = October 2017 | pmid = 28918903 | pmc = 5632562 | doi = 10.1016/j.molcel.2017.08.016 }}</ref> When [[Promoter (genetics)|promoters]] use the SAGA/TATA box complex to recruit RNA polymerase II, they are more highly regulated and display higher expression levels than promoters using the TFIID/TBP mode of recruitment.<ref name=":17" />

=== Analogous sequences ===
In bacteria, promoter regions may contain a [[Pribnow box]], which serves an analogous purpose to the eukaryotic TATA box. The Pribnow box has a 6 bp region centered around the -10 position and an 8-12 bp sequence around the -35 region that are both conserved.<ref name=":12" />

A [[CAAT box]] (also CAT box) is a region of nucleotides with the following consensus sequence: 5’ GGCCAATCT 3’. The CAAT box is located about 75-80 bases upstream of the transcription initiation site and about 150 bases upstream of the TATA box. It binds [[transcription factor]]s (CAAT TF or CTFs) and thereby stabilizes the nearby [[Transcription preinitiation complex|preinitiation complex]] for easier binding of [[RNA polymerase]]s.&nbsp;CAAT boxes are rarely found in genes that express proteins ubiquitous in all cell types.<ref name=":12" />

== Structure ==

=== Sequence and prevalence ===
[[File:TATA_box_mechanism.png|thumb|415x415px|'''Figure 2.''' Mechanism for transcription initiation at the TATA box. Transcription factors, TATA binding protein (TBP), and RNA polymerase II are all recruited to begin transcription.]]
The TATA box is a component of the eukaryotic [[Promoter (genetics)|core promoter]] and generally contains the [[consensus sequence]] 5'-TATA(A/T)A(A/T)-3'.<ref name=":4">{{cite book|title=Molecular biology of the gene|others=Watson, James D., 1928-|isbn=9780321762436|edition=Seventh|location=Boston|oclc=824087979|last1 = Watson|first1 = James D.|year=2014}}</ref> In yeast, for example, one study found that various ''[[Saccharomyces]]'' genomes had the consensus sequence 5'-TATA(A/T)A(A/T)(A/G)-3', yet only about 20% of yeast genes even contained the TATA sequence.<ref name=":3">{{cite journal | vauthors = Basehoar AD, Zanton SJ, Pugh BF | title = Identification and distinct regulation of yeast TATA box-containing genes | journal = Cell | volume = 116 | issue = 5 | pages = 699–709 | date = March 2004 | pmid = 15006352 | doi=10.1016/s0092-8674(04)00205-3| doi-access = free }}</ref> Similarly, in humans only 24% of genes have [[Promoter (genetics)|promoter]] regions containing the TATA box.<ref name=":2">{{cite journal | vauthors = Yang C, Bolotin E, Jiang T, Sladek FM, Martinez E | title = Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters | journal = Gene | volume = 389 | issue = 1 | pages = 52–65 | date = March 2007 | pmid = 17123746 | pmc = 1955227 | doi = 10.1016/j.gene.2006.09.029 }}</ref> Genes containing the TATA-box tend to be involved in [[Cellular stress response|stress-responses]] and certain types of [[metabolism]] and are more highly regulated when compared to TATA-less genes.<ref name=":3" /><ref name=":7">{{cite journal | vauthors = Bae SH, Han HW, Moon J | title = Functional analysis of the molecular interactions of TATA box-containing genes and essential genes | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0120848 | date = 2015 | pmid = 25789484 | pmc = 4366266 | doi = 10.1371/journal.pone.0120848 | bibcode = 2015PLoSO..1020848B | doi-access = free }}</ref> Generally, TATA-containing genes are not involved in essential cellular functions such as [[cell growth]], [[DNA replication]], [[Transcription (biology)|transcription]], and [[Translation (biology)|translation]] because of their highly regulated nature.<ref name=":7" />

The TATA box is usually located 25-35 base pairs upstream of the transcription start site. Genes containing the TATA box usually require additional promoter elements, including an [[Initiator element|initiator]] site located just [[Upstream and downstream (DNA)|upstream]] of the transcription start site and a [[Downstream promoter element|downstream core element]] (DCE).<ref name=":4" /> These additional promoter regions work in conjunction with the TATA box to regulate initiation of transcription in eukaryotes.

== Function ==

=== Role in transcription initiation ===
The TATA-box is the site of [[Transcription preinitiation complex|preinitiation complex]] formation, which is the first step in transcription initiation in eukaryotes. Formation of the preinitiation complex begins when the multi-subunit transcription factor II D ([[Transcription factor II D|TFIID]]) binds to the TATA box at its [[TATA-binding protein|TATA-binding protein (TBP)]] subunit.<ref name=":4" /> TBP binds to the [[minor groove]]<ref>{{cite journal | vauthors = Starr DB, Hawley DK | title = TFIID binds in the minor groove of the TATA box | journal = Cell | volume = 67 | issue = 6 | pages = 1231–40 | date = December 1991 | pmid = 1760847 | doi=10.1016/0092-8674(91)90299-e| s2cid = 10297041 }}</ref> of the TATA box via a region of antiparallel [[Beta sheet|β sheets]] in the protein.<ref name=":8"/> Three types of molecular interactions contribute to [[TATA-binding protein|TBP]] binding to the TATA box:
# Four [[phenylalanine]] residues(Phe57, Phe74, Phe148, Phe165) on TBP bind to DNA and form kinks in the DNA, forcing the DNA minor groove open.<ref name=":8">{{cite journal | vauthors = Kim JL, Nikolov DB, Burley SK | title = Co-crystal structure of TBP recognizing the minor groove of a TATA element | journal = Nature | volume = 365 | issue = 6446 | pages = 520–7 | date = October 1993 | pmid = 8413605 | doi = 10.1038/365520a0 | bibcode = 1993Natur.365..520K | s2cid = 4371241 }}</ref><ref name=":9">{{cite journal | vauthors = Nikolov DB, Chen H, Halay ED, Hoffman A, Roeder RG, Burley SK | title = Crystal structure of a human TATA box-binding protein/TATA element complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 10 | pages = 4862–7 | date = May 1996 | pmid = 8643494 | doi=10.1073/pnas.93.10.4862 | pmc=39370| bibcode = 1996PNAS...93.4862N | doi-access = free }}</ref><ref name=":10">{{cite journal | vauthors = Kim Y, Geiger JH, Hahn S, Sigler PB | title = Crystal structure of a yeast TBP/TATA-box complex | journal = Nature | volume = 365 | issue = 6446 | pages = 512–20 | date = October 1993 | pmid = 8413604 | doi = 10.1038/365512a0 | bibcode = 1993Natur.365..512K | s2cid = 4336203 }}</ref>
# Four [[hydrogen bond]]s form between polar side chains on TBP [[amino acid]] (Asn27, Asn117, Thr82, Thr173)( and [[Nucleobase|bases]] in the [[minor groove]].<ref name=":8" />
# Numerous [[Hydrophobe|hydrophobic]] interactions(~15) form between TBP residues(notably Ile152 and Leu163) and DNA [[Nucleobase|bases]], including [[Van der Waals force|van der Waals]] forces.<ref name=":8" /><ref name=":9" /><ref name=":10" />
Additionally, binding of [[TATA-binding protein|TBP]] is facilitated by stabilizing interactions with DNA flanking the TATA box, which consists of G-C rich sequences.<ref>{{cite journal | vauthors = Horikoshi M, Bertuccioli C, Takada R, Wang J, Yamamoto T, Roeder RG | title = Transcription factor TFIID induces DNA bending upon binding to the TATA element | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 3 | pages = 1060–4 | date = February 1992 | pmid = 1736286 | doi=10.1073/pnas.89.3.1060 | pmc=48385| bibcode = 1992PNAS...89.1060H | doi-access = free }}</ref> These secondary interactions induce bending of the DNA and helical unwinding.<ref>{{cite journal | vauthors = Blair RH, Goodrich JA, Kugel JF | title = Single-molecule fluorescence resonance energy transfer shows uniformity in TATA binding protein-induced DNA bending and heterogeneity in bending kinetics | journal = Biochemistry | volume = 51 | issue = 38 | pages = 7444–55 | date = September 2012 | pmid = 22934924 | pmc = 3551999 | doi = 10.1021/bi300491j }}</ref> The degree of DNA bending is species and sequence dependent. For example, one study used the adenovirus TATA promoter sequence (5'-CGC'''TATAAAAG'''GGC-3') as a model binding sequence and found that human TBP binding to the TATA box induced a 97° bend toward the [[Nucleic acid double helix|major groove]] while the yeast TBP protein only induced an 82° bend.<ref>{{cite journal | vauthors = Whittington JE, Delgadillo RF, Attebury TJ, Parkhurst LK, Daugherty MA, Parkhurst LJ | title = TATA-binding protein recognition and bending of a consensus promoter are protein species dependent | journal = Biochemistry | volume = 47 | issue = 27 | pages = 7264–73 | date = July 2008 | pmid = 18553934 | doi = 10.1021/bi800139w | s2cid = 7460689 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1005&context=chemistryparkhurst | url-access = subscription }}</ref> [[X-ray crystallography]] studies of TBP/TATA-box complexes generally agree that the DNA goes through an ~80° bend during the process of TBP-binding.<ref name=":8" /><ref name=":9" /><ref name=":10" />

The conformational changes induced by [[TATA-binding protein|TBP]] binding to the TATA box allows for additional [[transcription factor]]s and [[RNA polymerase II]] to bind to the [[Promoter (genetics)|promoter]] region. TFIID first binds to the TATA box, facilitated by [[TFIIA]] binding to the upstream part of the [[TFIID]] complex.<ref>{{cite journal | vauthors = Louder RK, He Y, López-Blanco JR, Fang J, Chacón P, Nogales E | title = Structure of promoter-bound TFIID and model of human pre-initiation complex assembly | journal = Nature | volume = 531 | issue = 7596 | pages = 604–9 | date = March 2016 | pmid = 27007846 | doi = 10.1038/nature17394 | pmc=4856295| bibcode = 2016Natur.531..604L }}</ref><ref>{{cite journal | vauthors = Wang J, Zhao S, He W, Wei Y, Zhang Y, Pegg H, Shore P, Roberts SG, Deng W | title = A transcription factor IIA-binding site differentially regulates RNA polymerase II-mediated transcription in a promoter context-dependent manner | journal = The Journal of Biological Chemistry | volume = 292 | issue = 28 | pages = 11873–11885 | date = July 2017 | pmid = 28539359 | pmc = 5512080 | doi = 10.1074/jbc.M116.770412 | doi-access = free }}</ref> [[TFIIB]] then binds to the TFIID-[[TFIIA]]-DNA complex through interactions both upstream and downstream of the TATA box.<ref name=":13">{{cite journal | vauthors = Krishnamurthy S, Hampsey M | title = Eukaryotic transcription initiation | journal = Current Biology | volume = 19 | issue = 4 | pages = R153–6 | date = February 2009 | pmid = 19243687 | doi = 10.1016/j.cub.2008.11.052 | doi-access = free }}</ref> [[RNA polymerase II]] is then recruited to this multi-protein complex with the help of [[TFIIF]].<ref name=":13" /> Additional transcription factors then bind, first [[TFIIE]] and then [[TFIIH]].<ref name=":13" /> This completes the assembly of the [[Transcription preinitiation complex|preinitiation complex]] for eukaryotic transcription.<ref name=":4" /> Generally, the TATA box is found at RNA polymerase II promoter regions, although some ''[[in vitro]]'' studies have demonstrated that [[RNA polymerase III]] can recognize TATA sequences.<ref>{{cite journal | vauthors = Duttke SH | title = RNA polymerase III accurately initiates transcription from RNA polymerase II promoters in vitro | journal = The Journal of Biological Chemistry | volume = 289 | issue = 29 | pages = 20396–404 | date = July 2014 | pmid = 24917680 | pmc = 4106352 | doi = 10.1074/jbc.M114.563254 | doi-access = free }}</ref>

This cluster of RNA polymerase II and various transcription factors is known as the basal transcriptional complex (BTC). In this state, it only gives a low level of transcription. Other factors must stimulate the BTC to increase transcription levels.<ref name=":11" /> One such example of a BTC stimulating region of DNA is the [[CAAT box]]. Additional factors, including the [[Mediator (coactivator)|Mediator complex]], transcriptional regulatory proteins, and [[nucleosome]]-modifying [[enzyme]]s also enhance [[Transcription (biology)|transcription]] ''[[in vivo]]''.<ref name=":4" />

=== Interactions ===
In specific cell types or on specific promoters TBP can be replaced by one of several TBP-related factors (TRF1 in [[Drosophila]], TBPL1/TRF2 in [[metazoa]]ns, TBPL2/TRF3 in [[vertebrate]]s), some of which interact with the TATA box similar to [[TATA-binding protein|TBP]].<ref>{{cite journal | vauthors = Akhtar W, Veenstra GJ | title = TBP-related factors: a paradigm of diversity in transcription initiation | journal = Cell & Bioscience | volume = 1 | issue = 1 | pages = 23 | date = 1 January 2011 | pmid = 21711503 | pmc = 3142196 | doi = 10.1186/2045-3701-1-23 | doi-access = free }}</ref> Interaction of TATA boxes with a variety of [[Activator (genetics)|activators]] or [[repressor]]s can influence the [[Transcription (biology)|transcription]] of [[gene]]s in many ways{{Citation needed|date=December 2018}}. [[Enhancer (genetics)|Enhancers]] are long-range regulatory elements that increase promoter activity while [[Silencer (genetics)|silencers]] repress promoter activity.

== Mutations ==
[[File:Mutation_mechanism.png|thumb|612x612px|'''Figure 3.''' Effects on TBP binding to the TATA box from mutations. Wildtype shows transcription done normally. An insertion or deletion shifts the TATA box recognition site which results in a shifted transcription site.<ref name=":5">{{cite journal | vauthors = Chioin R, Stritoni P, Scognamiglio R, Boffa GM, Daliento L, Razzolini R, Ramondo A, Dalla Volta S | title = [Natural history of coronary disease with and without aortocoronary by-pass operation. Survival curves of 272 patients over a maximum period of 24 months (author's transl)] | journal = Giornale Italiano di Cardiologia | volume = 8 | issue = 4 | pages = 359–64 | date = 1987 | pmc = 306359 | pmid=3671084| doi = 10.1093/nar/15.20.8283 }}</ref>  Point mutations risk the TBP being unable to bind for initiation.<ref name=":6">{{cite journal | vauthors = Gaillard J, Haguenauer JP, Romanet P, Boulud B, Gerard JP | title = [Tumors of the olfactory placode. Study of 5 cases] | journal = Journal Français d'Oto-Rhino-Laryngologie; Audiophonologie, Chirurgie Maxillo-Faciale | volume = 26 | issue = 9 | pages = 669–76 | date = November 1977 | pmc = 146060 | pmid=8760900| doi = 10.1093/nar/24.15.3100 }}</ref>]]
[[Mutation]]s to the TATA box can range from a [[Deletion (genetics)|deletion]] or [[Insertion (genetics)|insertion]] to a [[point mutation]] with varying effects based on the gene that has been mutated.  The [[mutation]]s change the binding of the [[TATA-binding protein|TATA-binding protein (TBP)]] for [[Transcription (biology)|transcription]] initiation. Thus, there is a resulting change in [[phenotype]] based on the gene that is not being [[Gene expression|expressed]] (Figure 3).

=== Insertions or deletions ===
One of the first studies of TATA box [[mutation]]s looked at a sequence of DNA from ''[[Agrobacterium tumefaciens]]'' for the octopine type [[Cytokinin signaling and response regulator protein|cytokinin gene]].<ref name=":5" /> This specific gene has three TATA boxes. A [[phenotype]] change was only observed when all three TATA boxes were deleted. An [[Insertion (genetics)|insertion]] of extra base pairs between the last TATA box and the transcription start site resulted in a shift in the start site; thus, resulting in a phenotypic change.&nbsp; From this original [[mutation]] study, a change in transcription can be seen when there is no TATA box to promote transcription, but transcription of a gene will occur when there is an [[Insertion (genetics)|insertion]] to the sequence.&nbsp;The nature of the resulting phenotype may be affected due to the [[Insertion (genetics)|insertion]].

[[Mutation]]s in [[maize]] [[Promoter (genetics)|promoters]] affect the expression of the [[Promoter (genetics)|promoter]] [[gene]]s in a plant-organ-specific manner.<ref name=":19">{{cite journal | vauthors = Kloeckener-Gruissem B, Vogel JM, Freeling M | title = The TATA box promoter region of maize Adh1 affects its organ-specific expression | journal = The EMBO Journal | volume = 11 | issue = 1 | pages = 157–66 | date = January 1992 | pmid = 1740103 | pmc=556436| doi = 10.1002/j.1460-2075.1992.tb05038.x }}</ref> A [[Duplication (chromosomal)|duplication]] of the TATA box leads to a significant decrease in [[Enzyme|enzymatic activity]] in the [[Scutellum (botany)|scutellum]] and [[root]]s, leaving [[pollen]] enzymatic levels unaffected. A [[Deletion (genetics)|deletion]] of the TATA box leads to a small decrease in [[Enzyme|enzymatic activity]] in the [[Scutellum (botany)|scutellum]] and [[root]]s, but a large decrease in [[Enzyme|enzymatic levels]] in [[pollen]].<ref name=":19" />

=== Point mutations ===
Point mutations to the TATA box have similar varying [[Phenotype|phenotypic]] changes depending on the gene that is being affected. Studies also show that the placement of the [[mutation]] in the TATA box sequence hinders the binding of [[TATA-binding protein|TBP]].<ref name=":6" /> For example, a [[mutation]] from TATAAAA to CATAAAA does completely hinder the binding sufficiently to change [[Transcription (biology)|transcription]], the neighboring sequences can affect if there is a change or not.<ref>{{cite journal | vauthors = Fei YJ, Stoming TA, Efremov GD, Efremov DG, Battacharia R, Gonzalez-Redondo JM, Altay C, Gurgey A, Huisman TH | title = Beta-thalassemia due to a T----A mutation within the ATA box | journal = Biochemical and Biophysical Research Communications | volume = 153 | issue = 2 | pages = 741–7 | date = June 1988 | pmid = 3382401 | doi = 10.1016/S0006-291X(88)81157-4 }}</ref> However, a change can be seen in [[HeLa]] cells with a TATAAAA to TATACAA which leads to a 20 fold decrease in [[Transcription (biology)|transcription]].<ref>{{cite journal | vauthors = Bower GC | title = The award of the Will Ross Medal for 1978 | journal = The American Review of Respiratory Disease | year = 1978 | volume = 118 | issue = 3 | pages = 635–636 | pmid= 360896 }}</ref> Some diseases that can be caused due to this insufficiency by specific gene [[Transcription (biology)|transcription]] are:&nbsp; [[Thalassemia]],<ref name="pmid6583702">{{cite journal | vauthors = Antonarakis SE, Irkin SH, Cheng TC, Scott AF, Sexton JP, Trusko SP, Charache S, Kazazian HH | title = beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 4 | pages = 1154–8 | year = 1984 | pmid = 6583702 | pmc = 344784 | doi =  10.1073/pnas.81.4.1154| bibcode = 1984PNAS...81.1154A | doi-access = free }}</ref> [[lung cancer]],<ref>{{cite journal | vauthors = Zienolddiny S, Ryberg D, Maggini V, Skaug V, Canzian F, Haugen A | title = Polymorphisms of the interleukin-1 beta gene are associated with increased risk of non-small cell lung cancer | journal = International Journal of Cancer | volume = 109 | issue = 3 | pages = 353–6 | date = April 2004 | pmid = 14961572 | doi = 10.1002/ijc.11695 | doi-access = free }}</ref> [[Hemolytic anemia|chronic hemolytic anemia]],<ref>{{cite journal | vauthors = Hildebrandt P | title = Subcutaneous absorption of insulin in insulin-dependent diabetic patients. Influence of species, physico-chemical properties of insulin and physiological factors | journal = Danish Medical Bulletin | volume = 38 | issue = 4 | pages = 337–46 | date = August 1991 | pmc = 1914533 | pmid=8571957}}</ref> [[immunosuppression]],<ref>{{cite journal | vauthors = Takahashi K, Ezekowitz RA | title = The role of the mannose-binding lectin in innate immunity | journal = Clinical Infectious Diseases | volume = 41 | pages = S440–4 | date = November 2005 | issue = Suppl 7 | pmid = 16237644 | doi = 10.1086/431987 | doi-access = free }}</ref> [[Haemophilia B|hemophilia B Leyden]],<ref>{{cite journal | vauthors = Sweet D, Golomb H, Desser R, Ultmann JE, Yachnin S, Stein R | title = Letter: Chemotherapy of advanced histocytic lymphomas | journal = Lancet | volume = 1 | issue = 7916 | pages = 6300–3 | date = May 1975 | pmc = 49488 | doi=10.1016/s0140-6736(75)92521-0 | pmid=1631121}}</ref> and [[thrombophlebitis]] and [[myocardial infarction]].<ref>{{cite journal | vauthors = Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C, Arveiler D, Luc G, Ruidavets JB, Emmerich J, Fiessinger JN, Aiach M | title = Polymorphisms in the 5' regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: the ECTIM and PATHROS studies. Etude Cas-Témoins de l'Infarctus du Myocarde. Paris Thrombosis case-control Study | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 20 | issue = 3 | pages = 892–8 | date = March 2000 | pmid = 10712418 | doi = 10.1161/01.ATV.20.3.892 | doi-access = free }}</ref>

Savinkova et al. has written a simulation to predict the ''[[Dissociation constant|K<sub>D</sub>]]'' value for a selected TATA box sequence and [[TATA-binding protein|TBP]].<ref name=":1">{{cite journal | vauthors = Savinkova L, Drachkova I, Arshinova T, Ponomarenko P, Ponomarenko M, Kolchanov N | title = An experimental verification of the predicted effects of promoter TATA-box polymorphisms associated with human diseases on interactions between the TATA boxes and TATA-binding protein | journal = PLOS ONE | volume = 8 | issue = 2 | pages = e54626 | date = 2013 | pmid = 23424617 | pmc = 3570547 | doi = 10.1371/journal.pone.0054626 | bibcode = 2013PLoSO...854626S | doi-access = free }}</ref> This can be used to directly predict the [[Phenotype|phenotypic]] traits resulting from a selected [[mutation]] based on how tightly [[TATA-binding protein|TBP]] is binding to the TATA box.

=== Diseases ===
[[Mutation]]s in the TATA box region affects the binding of the [[TATA-binding protein|TATA-binding protein (TBP)]] for transcription initiation, which may cause carriers to have a [[disease]] [[phenotype]].

[[Stomach cancer|Gastric cancer]] is correlated with TATA box [[Polymorphism (biology)|polymorphism]].<ref>{{cite journal| vauthors = De Re V, Magris R, De Zorzi M, Maiero S, Caggiari L, Fornasarig M, Repetto O, Buscarini E, Di Mario F | title = P.08.10: Interference of PG2 Tata Box Region with the Serum PG2 Level in Gastric Cancer|journal=Digestive and Liver Disease|volume=49|pages=e182–e183 | doi=10.1016/s1590-8658(17)30534-0| year=2017| s2cid = 79101992}}</ref> The TATA box has a binding site for the [[transcription factor]] of the PG2 gene. This gene produces PG2 serum, which is used as a [[biomarker]] for [[Neoplasm|tumours]] in gastric cancer. Longer TATA box sequences correlates with higher levels of PG2 serum indicating gastric cancer conditions. Carriers with shorter TATA box sequences may produce lower levels of PG2 serum.

Several [[neurodegenerative disorders]] are associated TATA box mutations.<ref>{{cite journal | vauthors = Roshan R, Choudhary A, Bhambri A, Bakshi B, Ghosh T, Pillai B | title = microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells | journal = Journal of Neuroinflammation | volume = 14 | issue = 1 | pages = 155 | date = August 2017 | pmid = 28774347 | doi = 10.1186/s12974-017-0925-3 | pmc=5543588 | doi-access = free }}</ref> Two disorders have been highlighted, [[spinocerebellar ataxia]] and [[Huntington's disease]]. In spinocerebellar ataxia, the disease phenotype is caused by expansion of the polyglutamine repeat in the [[TATA-binding protein|TATA-binding protein (TBP)]]. An accumulation of these polyglutamine-TBP cells will occur, as shown by protein aggregates in brain sections of patients, resulting in a loss of [[Neuron|neuronal cells]].

[[Visual impairment|Blindness]] can be caused by excessive [[cataract]] formation when the TATA box is targeted by [[microRNA]]s to increase the level of oxidative stress genes.<ref>{{cite journal | vauthors = Wu C, Liu Z, Ma L, Pei C, Qin L, Gao N, Li J, Yin Y | title = MiRNAs regulate oxidative stress related genes via binding to the 3' UTR and TATA-box regions: a new hypothesis for cataract pathogenesis | journal = BMC Ophthalmology | volume = 17 | issue = 1 | pages = 142 | date = August 2017 | pmid = 28806956 | doi = 10.1186/s12886-017-0537-9 | pmc=5556341 | doi-access = free }}</ref> MicroRNAs can target the [[Three prime untranslated region|3'-untranslated region]] and bind to the TATA box to activate the [[Transcription (biology)|transcription]] of oxidative stress related genes.

[[Single-nucleotide polymorphism|SNPs]] in TATA boxes are associated with [[Thalassemia|B-thalassemia]], [[immunosuppression]], and other [[neurological disorder]]s.<ref>{{cite journal | vauthors = Drachkova I, Savinkova L, Arshinova T, Ponomarenko M, Peltek S, Kolchanov N | title = The mechanism by which TATA-box polymorphisms associated with human hereditary diseases influence interactions with the TATA-binding protein | journal = Human Mutation | volume = 35 | issue = 5 | pages = 601–8 | date = May 2014 | pmid = 24616209 | doi = 10.1002/humu.22535 | s2cid = 19928327 | doi-access = free }}</ref> [[Single-nucleotide polymorphism|SNPs]] destabilize the TBP/TATA complex which significantly decreases the rate at which [[TATA-binding protein|TATA-binding proteins (TBP)]] will bind to the TATA box. This leads to lower levels of [[Transcription (biology)|transcription]] affecting the severity of the disease. Results from studies have shown the interaction in vitro so far, but results may be comparable to that in vivo.

[[Gilbert's syndrome]] is correlated with UTG1A1 TATA box [[Polymorphism (biology)|polymorphism]].<ref>{{cite journal | vauthors = Žaja O, Tiljak MK, Štefanović M, Tumbri J, Jurčić Z | title = Correlation of UGT1A1 TATA-box polymorphism and jaundice in breastfed newborns-early presentation of Gilbert's syndrome | journal = The Journal of Maternal-Fetal & Neonatal Medicine | volume = 27 | issue = 8 | pages = 844–50 | date = May 2014 | pmid = 23981182 | doi = 10.3109/14767058.2013.837879 | s2cid = 29893463 }}</ref> This poses a risk for developing jaundice in newborns.

[[MicroRNA]]s also play a role in replicating [[virus]]es such as [[Subtypes of HIV|HIV-1]].<ref>{{cite journal | vauthors = Zhang Y, Fan M, Geng G, Liu B, Huang Z, Luo H, Zhou J, Guo X, Cai W, Zhang H | title = A novel HIV-1-encoded microRNA enhances its viral replication by targeting the TATA box region | journal = Retrovirology | volume = 11 | pages = 23 | date = March 2014 | pmid = 24620741 | pmc = 4007588 | doi = 10.1186/1742-4690-11-23 | doi-access = free }}</ref> Novel HIV-1-encoded microRNA have been found to enhance the production of the virus as well as activating HIV-1 latency by targeting the TATA box region.

== Clinical significance ==

=== Technology ===
Many of the studies so far have been performed [[in vitro]], providing only a prediction of what may happen not a real-time representation of what is happening in the [[Cell (biology)|cells]]. Recent studies in 2016 have been done to demonstrate TATA-binding activity [[in vivo]]. Core [[Promoter (genetics)|promoter]]-specific mechanisms for transcription initiation by the canonical TBP/TFIID-dependent basal [[Transcription (biology)|transcription]] machinery has recently been documented [[in vivo]] showing the activation by [[Serum response factor|SRF]]-dependent [[Upstream activating sequence|upstream activating sequence (UAS)]] of the human [[ACTB (gene)|ACTB gene]] involved in TATA-binding.<ref name=":16">{{cite journal | vauthors = Xu M, Gonzalez-Hurtado E, Martinez E | title = Core promoter-specific gene regulation: TATA box selectivity and Initiator-dependent bi-directionality of serum response factor-activated transcription | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1859 | issue = 4 | pages = 553–63 | date = April 2016 | pmid = 26824723 | pmc = 4818687 | doi = 10.1016/j.bbagrm.2016.01.005 }}</ref>

=== Cancer therapy ===
[[Pharmaceutical companies]] have been designing [[cancer therapy]] [[drug]]s to target [[DNA]] in traditional methods over the years, and have proven to be successful.<ref name=":20">{{cite journal | vauthors = Hurley LH | title = DNA and its associated processes as targets for cancer therapy | journal = Nature Reviews. Cancer | volume = 2 | issue = 3 | pages = 188–200 | date = March 2002 | pmid = 11990855 | doi = 10.1038/nrc749 | s2cid = 24209612 }}</ref> However, the toxicity of these drugs have pushed scientists to explore other processes related to DNA that could be targeted instead. In recent years, a collective effort has been made to find cancer-specific molecular targets, such as protein-DNA complexes, which include the TATA binding motif. Compounds that trap the [[Protein-DNA complex|protein-DNA]] intermediate could result in it being [[Toxicity|toxic]] to the [[Cell (biology)|cell]] once they encounter a [[DNA]] processing event. Example of [[drug]]s that contain such compounds include [[topotecan]], [[SN-38]] ([[topoisomerase I]]), [[doxorubicin]], and [[mitoxantrone]] ([[topoisomerase II]]).<ref name=":20" /> [[Cisplatin]] is a compound that binds [[Covalent bond|covalently]] to adjacent [[guanine]]s in the [[Nucleic acid double helix|major groove]] of [[DNA]], which distorts [[DNA]] to allow access of [[DNA-binding protein]]s in the [[Nucleic acid double helix|minor groove]].<ref name=":20" /> This will destabilize the interaction between the [[TATA-binding protein|TATA-binding protein (TBP)]] to the TATA box. The result is to immobilize the [[TATA-binding protein|TATA-binding protein (TBP)]] on DNA in order to down-regulate [[Transcription (biology)|transcription]] initiation.

== Genetic engineering ==

=== TATA box modification ===
Evolutionary changes have pushed [[plant]]s to adapt to the changing environmental conditions. In the [[history]] of [[Earth]], the development of Earth's aerobic [[Atmosphere of Earth|atmosphere]] resulted in an [[iron]] deficiency in plants.<ref name=":15">{{cite journal | vauthors = Zhang M, Lv Y, Wang Y, Rose JK, Shen F, Han Z, Zhang X, Xu X, Wu T, Han Z | title = TATA Box Insertion Provides a Selection Mechanism Underpinning Adaptations to Fe Deficiency | journal = Plant Physiology | volume = 173 | issue = 1 | pages = 715–727 | date = January 2017 | pmid = 27881725 | doi = 10.1104/pp.16.01504 | pmc=5210749}}</ref> Compared to other members of the same species, ''[[Malus baccata]]'' var. ''xiaojinensis'' has a TATA box inserted in the promoter upstream of the iron-regulated transporter 1 (IRT1) [[Promoter (genetics)|promoter]]. As a result, the promoter activity levels are enhanced, increasing [[TFIID]] activity and subsequently [[Transcription (biology)|transcription initiation]], resulting in a more iron-efficient phenotype. With genetic engineering, a similar modification can be done to other plants, such as the model species of [[tobacco]] and ''[[Arabidopsis thaliana]]''.<!-- The study only performs transient expression to prove the causation between TATA insertion and increased expression. --><ref name=":15" />

== See also ==
* [[Pribnow box]]
* [[Initiator element]]
* [[Kozak consensus sequence]]

== References ==
<references />{{Transcription}}

[[Category:Regulatory sequences]]
[[Category:1978 in biology]]