Editing Messenger RNA (section)

==Degradation==
Different mRNAs within the same cell have distinct lifetimes (stabilities). In bacterial cells, individual mRNAs can survive from seconds to more than an hour. However, the lifetime averages between 1 and 3 minutes, making bacterial mRNA much less stable than eukaryotic mRNA.<ref>{{Cite book|title=Lewin's genes X|date=2011|publisher=Jones and Bartlett| veditors = Lewin B, Krebs JE, Kilpatrick ST, Goldstein ES |editor-link1=Benjamin Lewin |isbn=9780763766320|edition=10th|location=Sudbury, Mass.|oclc=456641931|url-access=registration|url=https://archive.org/details/lewinsgenesx0000unse}}</ref> In mammalian cells, mRNA lifetimes range from several minutes to days.<ref>{{cite journal | vauthors = Yu J, Russell JE | title = Structural and functional analysis of an mRNP complex that mediates the high stability of human beta-globin mRNA | journal = Molecular and Cellular Biology | volume = 21 | issue = 17 | pages = 5879–5888 | date = September 2001 | pmid = 11486027 | pmc = 87307 | doi = 10.1128/mcb.21.17.5879-5888.2001 }}</ref> The greater the stability of an mRNA the more protein may be produced from that mRNA. The limited lifetime of mRNA enables a cell to alter protein synthesis rapidly in response to its changing needs. There are many mechanisms that lead to the destruction of an mRNA, some of which are described below.

===Prokaryotic mRNA degradation===
[[File:1-s2.0-S1874939913000436-gr1 lrg.jpg|thumb|Overview of mRNA decay pathways in the different life domains.]]
In general, in prokaryotes the lifetime of mRNA is much shorter than in eukaryotes. Prokaryotes degrade messages by using a combination of ribonucleases, including [[endonuclease]]s, 3' [[exonuclease]]s, and 5' exonucleases. In some instances, [[small RNA|small RNA molecules]] (sRNA) tens to hundreds of nucleotides long can stimulate the degradation of specific mRNAs by base-pairing with complementary sequences and facilitating ribonuclease cleavage by [[RNase III]]. It was recently shown that bacteria also have a sort of [[5' cap]] consisting of a triphosphate on the [[5' end]].<ref name=Deana2008>{{cite journal | vauthors = Deana A, Celesnik H, Belasco JG | title = The bacterial enzyme RppH triggers messenger RNA degradation by 5' pyrophosphate removal | journal = Nature | volume = 451 | issue = 7176 | pages = 355–358 | date = January 2008 | pmid = 18202662 | doi = 10.1038/nature06475 | bibcode = 2008Natur.451..355D | s2cid = 4321451 }}</ref> Removal of two of the phosphates leaves a 5' monophosphate, causing the message to be destroyed by the exonuclease RNase J, which degrades 5' to 3'.

===Eukaryotic mRNA turnover===
Inside eukaryotic cells, there is a balance between the processes of [[Translation (genetics)|translation]] and mRNA decay. Messages that are being actively translated are bound by [[ribosome]]s, the [[eukaryotic initiation factor]]s [[eIF-4E]] and [[eIF-4G]], and [[poly(A)-binding protein]]. eIF-4E and eIF-4G block the decapping enzyme ([[DCP2]]), and poly(A)-binding protein blocks the [[exosome complex]], protecting the ends of the message. The balance between translation and decay is reflected in the size and abundance of cytoplasmic structures known as [[P-bodies]].<ref name=Parker2007>{{cite journal | vauthors = Parker R, Sheth U | title = P bodies and the control of mRNA translation and degradation | journal = Molecular Cell | volume = 25 | issue = 5 | pages = 635–646 | date = March 2007 | pmid = 17349952 | doi = 10.1016/j.molcel.2007.02.011 | doi-access = free }}</ref> The [[polyadenylation|poly(A) tail]] of the mRNA is shortened by specialized exonucleases that are targeted to specific messenger RNAs by a combination of cis-regulatory sequences on the RNA and trans-acting RNA-binding proteins. Poly(A) tail removal is thought to disrupt the circular structure of the message and destabilize the [[cap binding complex]]. The message is then subject to degradation by either the [[exosome complex]] or the [[decapping complex]]. In this way, translationally inactive messages can be destroyed quickly, while active messages remain intact. The mechanism by which translation stops and the message is handed-off to decay complexes is not understood in detail. The majority of mRNA decay was believed to be cytoplasmic; however, recently, a novel mRNA decay pathway was described, which starts in the nucleus.<ref name=Chattopadhyay2022>{{cite journal | vauthors = Chattopadhyay S, Garcia Martinez J, Haimovich G, Fischer J, Khwaja A, Barkai O, Chuartzman SG, Schuldiner M, Elran R, Rosenberg M, Urim S, Deshmukh S, Bohnsack K, Bohnsack M, Perez Ortin J, Choder M | title = RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and a novel mRNA decay pathway | journal = Nature Communications | volume = 13(1): 7184 | date = November 2022 | issue = 1 | page = 7184 | pmid = 36418294 | doi = 10.1038/s41467-022-34417-z | doi-access = free | pmc = 9684461 | bibcode = 2022NatCo..13.7184C }}</ref>

===AU-rich element decay===
The presence of [[AU-rich element]]s in some mammalian mRNAs tends to destabilize those transcripts through the action of cellular proteins that bind these sequences and stimulate [[poly(A)]] tail removal. Loss of the poly(A) tail is thought to promote mRNA degradation by facilitating attack by both the [[exosome complex]]<ref name=Chen2001>{{cite journal | vauthors = Chen CY, Gherzi R, Ong SE, Chan EL, Raijmakers R, Pruijn GJ, Stoecklin G, Moroni C, Mann M, Karin M | title = AU binding proteins recruit the exosome to degrade ARE-containing mRNAs | journal = Cell | volume = 107 | issue = 4 | pages = 451–464 | date = November 2001 | pmid = 11719186 | doi = 10.1016/S0092-8674(01)00578-5 | s2cid = 14817671 | doi-access = free }}</ref> and the [[decapping complex]].<ref>{{cite journal | vauthors = Fenger-Grøn M, Fillman C, Norrild B, Lykke-Andersen J | title = Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping | journal = Molecular Cell | volume = 20 | issue = 6 | pages = 905–915 | date = December 2005 | pmid = 16364915 | doi = 10.1016/j.molcel.2005.10.031 | doi-access = free }}</ref> Rapid mRNA degradation via [[AU-rich element]]s is a critical mechanism for preventing the overproduction of potent cytokines such as tumor necrosis factor (TNF) and granulocyte-macrophage colony stimulating factor (GM-CSF).<ref name="Shaw1986">{{cite journal | vauthors = Shaw G, Kamen R | title = A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation | journal = Cell | volume = 46 | issue = 5 | pages = 659–667 | date = August 1986 | pmid = 3488815 | doi = 10.1016/0092-8674(86)90341-7 | s2cid = 40332253 }}</ref> AU-rich elements also regulate the biosynthesis of proto-oncogenic transcription factors like [[c-Jun]] and [[c-Fos]].<ref name=Chen1995>{{cite journal | vauthors = Chen CY, Shyu AB | title = AU-rich elements: characterization and importance in mRNA degradation | journal = Trends in Biochemical Sciences | volume = 20 | issue = 11 | pages = 465–470 | date = November 1995 | pmid = 8578590 | doi = 10.1016/S0968-0004(00)89102-1 }}</ref>

===Nonsense-mediated decay===
{{main|Nonsense-mediated decay}}

Eukaryotic messages are subject to surveillance by [[nonsense-mediated decay]] (NMD), which checks for the presence of premature stop codons (nonsense codons) in the message. These can arise via incomplete splicing, [[V(D)J recombination]] in the [[adaptive immune system]], mutations in DNA, transcription errors, [[leaky scanning]] by the ribosome causing a [[frame shift]], and other causes. Detection of a premature stop codon triggers mRNA degradation by 5' decapping, 3' [[poly(A)]] tail removal, or [[endonuclease|endonucleolytic cleavage]].<ref name=Isken2007>{{cite journal | vauthors = Isken O, Maquat LE | title = Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function | journal = Genes & Development | volume = 21 | issue = 15 | pages = 1833–1856 | date = August 2007 | pmid = 17671086 | doi = 10.1101/gad.1566807 | doi-access = free }}</ref>

===Small interfering RNA (siRNA)===
{{main|siRNA}}

In [[metazoan]]s, [[small interfering RNA]]s (siRNAs) processed by [[Dicer]] are incorporated into a complex known as the [[RNA-induced silencing complex]] or RISC. This complex contains an [[endonuclease]] that cleaves perfectly complementary messages to which the siRNA binds. The resulting mRNA fragments are then destroyed by [[exonuclease]]s. siRNA is commonly used in laboratories to block the function of genes in cell culture. It is thought to be part of the innate immune system as a defense against double-stranded RNA viruses.<ref name=Obbard2009>{{cite journal | vauthors = Obbard DJ, Gordon KH, Buck AH, Jiggins FM | title = The evolution of RNAi as a defence against viruses and transposable elements | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 364 | issue = 1513 | pages = 99–115 | date = January 2009 | pmid = 18926973 | pmc = 2592633 | doi = 10.1098/rstb.2008.0168 }}</ref>

===MicroRNA (miRNA)===
{{main|microRNA}}

MicroRNAs (miRNAs) are small RNAs that typically are partially complementary to sequences in metazoan messenger RNAs.<ref>Robert E. Farrell, Jr. RNA Methodologies, 5th Edition. Academic Press, 2017</ref><ref>{{cite journal | vauthors = Brennecke J, Stark A, Russell RB, Cohen SM | title = Principles of microRNA-target recognition | journal = PLOS Biology | volume = 3 | issue = 3 | pages = e85 | date = March 2005 | pmid = 15723116 | pmc = 1043860 | doi = 10.1371/journal.pbio.0030085 | doi-access = free }}</ref> Binding of a miRNA to a message can repress translation of that message and accelerate poly(A) tail removal, thereby hastening mRNA degradation. The mechanism of action of miRNAs is the subject of active research.<ref>Tasuku Honjo, Michael Reth, Andreas Radbruch, Frederick Alt. Molecular Biology of B Cells, 2nd Edition. Academic Press, 2014 (including "updated research on microRNAs")</ref><ref name=Eulalio2009>{{cite journal | vauthors = Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E | title = Deadenylation is a widespread effect of miRNA regulation | journal = RNA | volume = 15 | issue = 1 | pages = 21–32 | date = January 2009 | pmid = 19029310 | pmc = 2612776 | doi = 10.1261/rna.1399509 }}</ref>

===Other decay mechanisms===
There are other ways by which messages can be degraded, including [[non-stop decay]] and silencing by [[Piwi-interacting RNA]] (piRNA), among others.