Editing Terminator (genetics) (section)

==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>