Editing Terminator (genetics)

{{short description|Section of genetic sequence that marks the end of gene or operon on genomic DNA for transcription}}

In [[genetics]], a '''transcription terminator''' is a section of [[nucleic acid]] sequence that marks the end of a [[gene]] or [[operon]] in genomic [[DNA]] during [[Transcription (genetics)|transcription]]. This sequence mediates transcriptional termination by providing signals in the newly synthesized transcript RNA that trigger processes which release the  transcript RNA from the [[RNA polymerase|transcriptional complex]]. These processes include the direct interaction of the [[Nucleic acid secondary structure|mRNA secondary structure]] with the complex and/or the indirect activities of recruited [[termination factor]]s. Release of the transcriptional complex frees [[RNA polymerase]] and related transcriptional machinery to begin transcription of new mRNAs.

==In prokaryotes==
{{missing information|section|archaea, which has a more relaxed intrinsic ("rho-indep") requirement; archaeal FttA ({{PMID|33112729}})|date=December 2023}}
[[File:Prokaryotic terminators-en.svg|thumb|Simplified schematics of the mechanisms of prokaryotic transcriptional termination. In Rho-independent termination, a terminating hairpin forms on the nascent mRNA interacting with the NusA protein to stimulate release of the transcript from the RNA polymerase complex (top). In Rho-dependent termination, the Rho protein binds at the upstream rut site, translocates down the mRNA, and interacts with the RNA polymerase complex to stimulate release of the transcript.]]
Two classes of transcription terminators, Rho-dependent and Rho-independent, have been identified throughout [[prokaryotes|prokaryotic]] genomes. These widely distributed sequences are responsible for triggering the end of transcription upon normal completion of gene or [[operon]] transcription, mediating early termination of transcripts as a means of regulation such as that observed in [[attenuator (genetics)|transcriptional attenuation]], and to ensure the termination of runaway transcriptional complexes that manage to escape earlier terminators by chance, which prevents unnecessary energy expenditure for the cell.

===Rho-dependent terminators===
Rho-dependent transcription terminators require a large protein called a [[Rho factor]] which exhibits RNA [[helicase]] activity to disrupt the mRNA-DNA-RNA polymerase transcriptional complex. Rho-dependent terminators are found in [[bacteria]] and [[phage|phages]]. The Rho-dependent terminator occurs downstream of translational [[stop codon]]s and consists of an unstructured, cytosine-rich sequence on the mRNA known as a [[Rho utilisation site|Rho utilization site]] (''rut''),<ref>{{cite journal |last1=Di Salvo |first1=Marco |last2=Puccio |first2=Simone |last3=Peano |first3=Clelia |last4=Lacour |first4=Stephan |last5=Alifano |first5=Pietro |title=RhoTermPredict: an algorithm for predicting Rho-dependent transcription terminators based on Escherichia coli, Bacillus subtilis and Salmonella enterica databases |journal=BMC Bioinformatics |date=7 March 2019 |volume=20 |issue=1 |page=117 |doi=10.1186/s12859-019-2704-x |pmid=30845912 |pmc=6407284 |doi-access=free}}</ref> and a downstream transcription stop point (''tsp''). The ''rut'' serves as a mRNA loading site and as an activator for Rho; activation enables Rho to efficiently hydrolyze [[Adenosine triphosphate|ATP]] and translocate down the mRNA while it maintains contact with the rut site. Rho is able to catch up with the RNA polymerase because it is being stalled at the downstream ''tsp'' sites. Multiple different sequences can function as a tsp site.<ref name="Richardson1996">{{cite journal|last1=Richardson|first1=J. P.|title=Rho-dependent Termination of Transcription Is Governed Primarily by the Upstream Rho Utilization (rut) Sequences of a Terminator|journal=Journal of Biological Chemistry|volume=271|issue=35|year=1996|pages=21597–21603|issn=0021-9258|doi=10.1074/jbc.271.35.21597|pmid=8702947|doi-access=free}}</ref> Contact between Rho and the RNA polymerase complex stimulates dissociation of the transcriptional complex through a mechanism involving [[allosteric regulation|allosteric effects]] of Rho on RNA polymerase.<ref name="Ciampi-2006">{{Cite journal  | last1 = Ciampi | first1 = MS. | title = Rho-dependent terminators and transcription termination | journal = Microbiology | volume = 152 | issue = Pt 9 | pages = 2515–28 |date=Sep 2006 | doi = 10.1099/mic.0.28982-0 | pmid = 16946247 | doi-access = free }}</ref><ref>{{cite journal|last=Epshtein|first=V|author2=Dutta, D |author3=Wade, J |author4= Nudler, E |title=An allosteric mechanism of Rho-dependent transcription termination.|journal=Nature|date=Jan 14, 2010|volume=463|issue=7278|pages=245–9|pmid=20075920|doi=10.1038/nature08669 |pmc=2929367|bibcode=2010Natur.463..245E}}</ref>

===Rho-independent terminators===
{{main|Intrinsic termination}}
[[Intrinsic termination|Intrinsic transcription terminators]] or Rho-independent terminators require the formation of a [[Nucleic acid thermodynamics|self-annealing]] [[Hairpin (genetics)|hairpin]] structure on the elongating transcript, which results in the disruption of the [[polymerase|mRNA-DNA-RNA polymerase ternary complex]]. The terminator sequence in DNA contains a 20 basepair GC-rich region of [[dyad symmetry]] followed by a short poly-A tract or "A stretch" which is transcribed to form the terminating hairpin and a 7–9 nucleotide "U tract" respectively. The mechanism of termination is hypothesized to occur through a combination of direct promotion of dissociation through [[allosteric regulation|allosteric effects]] of hairpin binding interactions with the RNA polymerase and "competitive kinetics".  The hairpin formation causes RNA polymerase stalling and destabilization, leading to a greater likelihood that dissociation of the complex will occur at that location due to increased time spent paused at that site and reduced stability of the complex.<ref name="von Hippel1998">{{cite journal|last1=von Hippel|first1=P. H.|title=An Integrated Model of the Transcription Complex in Elongation, Termination, and Editing|journal=Science|volume=281|issue=5377|year=1998|pages=660–665|doi=10.1126/science.281.5377.660|pmid=9685251|bibcode=1998Sci...281..660.|s2cid=11046390}}</ref><ref name="GusarovNudler1999">{{cite journal|last1=Gusarov|first1=Ivan|last2=Nudler|first2=Evgeny|title=The Mechanism of Intrinsic Transcription Termination|journal=Molecular Cell|volume=3|issue=4|year=1999|pages=495–504|issn=1097-2765|doi=10.1016/S1097-2765(00)80477-3|pmid=10230402|doi-access=free}}</ref>
Additionally, the elongation protein factor NusA interacts with the RNA polymerase and the hairpin structure to stimulate transcriptional termination.<ref name="Santangelo-2011">{{Cite journal  | last1 = Santangelo | first1 = TJ. | last2 = Artsimovitch | first2 = I. | title = Termination and antitermination: RNA polymerase runs a stop sign. | journal = Nat Rev Microbiol | volume = 9 | issue = 5 | pages = 319–29 |date=May 2011 | doi = 10.1038/nrmicro2560 | pmid = 21478900 | pmc=3125153}}</ref>

==In eukaryotes==
In [[eukaryotes|eukaryotic]] transcription of mRNAs, terminator signals are recognized by protein factors that are associated with the [[RNA polymerase II]] and which trigger the termination process. The genome encodes one or more [[Polyadenylation#Mechanism|polyadenylation signal]]s. Once the signals are transcribed into the mRNA, the proteins [[CPSF|cleavage and polyadenylation specificity factor (CPSF)]] and [[cleavage stimulation factor|cleavage stimulation factor (CstF)]] transfer from the [[C-terminus|carboxyl terminal]] domain of RNA polymerase II to the poly-A signal. These two factors then recruit other proteins to the site to cleave the transcript, freeing the mRNA from the transcription complex, and add a string of about 200 A-repeats to the 3' end of the mRNA in a process known as [[polyadenylation]]. During these processing steps, the RNA polymerase continues to transcribe for several hundred to a few thousand bases and eventually dissociates from the DNA and downstream transcript through an unclear mechanism; there are two basic models for this event known as the torpedo and allosteric models.<ref name="Watson 2008 410–411">{{cite book|last=Watson|first=J.|title=Molecular Biology of the Gene|year=2008|publisher=Cold Spring Harbor Laboratory Press|isbn=978-0-8053-9592-1|pages=410–411}}</ref><ref name="Roso05">{{Cite journal|last1=Rosonina|first1=Emanuel|last2=Kaneko|first2=Syuzo|last3=Manley|first3=James L.|date=2006-05-01|title=Terminating the transcript: breaking up is hard to do|journal=Genes & Development|language=en|volume=20|issue=9|pages=1050–1056|doi=10.1101/gad.1431606|issn=0890-9369|pmid=16651651|doi-access=free}}</ref>

===Torpedo model===
After the mRNA is completed and cleaved off at the poly-A signal sequence, the left-over (residual) RNA strand remains bound to the DNA template and the [[RNA polymerase II]] unit, continuing to be transcribed. After this cleavage, a so-called [[exonuclease]] binds to the residual RNA strand and removes the freshly transcribed nucleotides one at a time (also called 'degrading' the RNA), moving towards the bound RNA polymerase II. This exonuclease is [[XRN2]] (5'-3' Exoribonuclease 2) in humans. This model proposes that XRN2 proceeds to degrade the uncapped residual RNA from 5' to 3' until it reaches the RNA pol II unit. This causes the exonuclease to 'push off' the RNA pol II unit as it moves past it, terminating the transcription while also cleaning up the residual RNA strand.

Similar to Rho-dependent termination, XRN2 triggers the dissociation of RNA polymerase II by either pushing the polymerase off of the DNA template or pulling the template out of the RNA polymerase.<ref>{{cite journal|last=Luo|first=W.|author2=Bartley D. |title=A ribonucleolytic rat torpedoes RNA polymerase II|journal=Cell|year=2004|volume=119|pages=911–914 | pmid = 15620350|doi=10.1016/j.cell.2004.11.041|issue=7|doi-access=free}}</ref> The mechanism by which this happens remains unclear, however, and has been challenged not to be the sole cause of the dissociation.<ref>{{Cite journal|last1=Luo|first1=Weifei|last2=Johnson|first2=Arlen W.|last3=Bentley|first3=David L.|date=2006-04-15|title=The role of Rat1 in coupling mRNA 3′-end processing to transcription termination: implications for a unified allosteric–torpedo model|journal=Genes & Development|language=en|volume=20|issue=8|pages=954–965|doi=10.1101/gad.1409106|issn=0890-9369|pmc=1472303|pmid=16598041}}</ref>

In order to protect the transcribed mRNA from degradation by the exonuclease, a [[5' cap]] is added to the strand. This is a modified guanine added to the front of mRNA, which prevents the exonuclease from binding and degrading the RNA strand. A 3' [[poly(A) tail]] is added to the end of a mRNA strand for protection from other exonucleases as well.

===Allosteric model===
The allosteric model suggests that termination occurs due to the structural change of the RNA polymerase unit after binding to or losing some of its associated proteins, making it detach from the DNA strand after the signal.<ref name="Roso05" /> This would occur after the RNA pol II unit has transcribed the poly-A signal sequence, which acts as a terminator signal.

RNA polymerase is normally capable of transcribing DNA into single-stranded mRNA efficiently. However, upon transcribing over the poly-A signals on the DNA template, a conformational shift is induced in the RNA polymerase from the proposed loss of associated proteins from its [[C-terminus|carboxyl terminal domain]]. This change of conformation reduces RNA polymerase's [[processivity]] making the enzyme more prone to dissociating from its DNA-RNA substrate. In this case, termination is not completed by degradation of mRNA but instead is mediated by limiting the elongation efficiency of RNA polymerase and thus increasing the likelihood that the polymerase will dissociate and end its current cycle of transcription.<ref name="Watson 2008 410–411" />

===Non-mRNAs===
The several RNA polymerases in eukaryotes each have their own means of termination. [[RNA polymerase I|Pol I]] is stopped by [[TTF1]] (yeast Nsi1), which recognizes a downstream DNA sequence; the endonuclease is [[XRN2]] (yeast Rat1). Pol III is able to terminate transcription on a stretch of As on the template strand.<ref>{{cite journal |last1=Arimbasseri |first1=AG |last2=Rijal |first2=K |last3=Maraia |first3=RJ |title=Transcription termination by the eukaryotic RNA polymerase III. |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |date=March 2013 |volume=1829 |issue=3–4 |pages=318–30 |doi=10.1016/j.bbagrm.2012.10.006 |pmid=23099421 |pmc=3568203}}</ref>

Finally, Pol II also have poly(A)-independent modes of termination, which is required when it transcribes snRNA and snoRNA genes. In yeast, the protein ''[[SCAF4|Nrd1]]'' is responsible,<ref name="Roso05"/> along with ''Nab3'' (multiple human homologs including [[HNRNPC]] and [[RALY]])<ref>{{cite web |title=NAB3 {{!}} SGD |url=https://www.yeastgenome.org/locus/S000006111 |website=www.yeastgenome.org}}</ref> and ''[[SETX|Sen1]]'', collectively making up the "NNS" pathway.<ref>{{cite journal |last1=Xiong |first1=Ying |last2=Han |first2=Weijing |last3=Xu |first3=Chunhua |last4=Shi |first4=Jing |last5=Wang |first5=Lisha |last6=Jin |first6=Taoli |last7=Jia |first7=Qi |last8=Lu |first8=Ying |last9=Hu |first9=Shuxin |last10=Dou |first10=Shuo-Xing |last11=Lin |first11=Wei |last12=Strick |first12=Terence R. |last13=Wang |first13=Shuang |last14=Li |first14=Ming |title=Single-molecule reconstruction of eukaryotic factor-dependent transcription termination |journal=Nature Communications |date=15 June 2024 |volume=15 |issue=1 |doi=10.1038/s41467-024-49527-z|pmc=11180205 }}</ref>

Some human mechanism, possibly [[PCF11]], seems to cause premature termination when pol II transcribes HIV genes.<ref>{{cite journal |last1=Gilmour |first1=David S. |last2=Fan |first2=Ruopeng |title=Derailing the Locomotive: Transcription Termination |journal=Journal of Biological Chemistry |date=January 2008 |volume=283 |issue=2 |pages=661–664 |doi=10.1074/jbc.R700032200|doi-access=free|pmid=17998201 }}</ref>

==See also==
*[[Termination codon|Stop codon]]
*[[Termination factor]]
*[[Transcription (biology)]]

==References==
{{reflist}}

==External links==
* {{MeshName|Terminator+Sequence}}

{{Transcription}}

[[Category:Gene expression]]