View source for SymE-SymR toxin-antitoxin system

{{Infobox rfam
| Name = SymR
| image = SymR_SScons.png
| width =
| caption = Conserved secondary structure of SymR RNA.
| Symbol = SymR
| AltSymbols =
| Rfam = RF01809
| RNA_type = [[Antisense RNA]]
| Tax_domain = ''[[Escherichia coli|E. coli]]''
}}
{{Infobox protein family
| Symbol = SymE_toxin
| Name =  SymE Toxin of Type I toxin-antitoxin system
| image =[[File:SymE Toxin.png|SymE Toxin|right|300px]]
| width = 
| caption =SymE Toxin of Type I toxin-antitoxin system
| Pfam = PF13957
| Pfam_clan =  
| InterPro =IPR020883
| SMART =
| PROSITE =PS51740 
| MEROPS = 
| SCOP =
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
|below=https://swissmodel.expasy.org/repository/uniprot/P39394}}
__NOTOC__
The '''SymE-SymR toxin-antitoxin system''' consists of a small symbiotic [[Endonuclease/Exonuclease/phosphatase family|endonuclease]] toxin, SymE, and a [[non-coding RNA]] [[Symbiosis|symbiotic]] RNA antitoxin, SymR, which inhibits SymE translation.<ref name="Kaw07">{{cite journal | vauthors = Kawano M, Aravind L, Storz G | title = An antisense RNA controls synthesis of an SOS-induced toxin evolved from an antitoxin | journal = Molecular Microbiology | volume = 64 | issue = 3 | pages = 738–54 | date = May 2007 | pmid = 17462020 | pmc = 1891008 | doi = 10.1111/j.1365-2958.2007.05688.x }}</ref> SymE-SymR is a type I toxin-antitoxin system, and is under regulation by the antitoxin, SymR.<ref name=":0">{{cite journal | vauthors = Kawano M | title = Divergently overlapping cis-encoded antisense RNA regulating toxin-antitoxin systems from E. coli: hok/sok, ldr/rdl, symE/symR | journal = RNA Biology | volume = 9 | issue = 12 | pages = 1520–7 | date = December 2012 | pmid = 23131729 | doi = 10.4161/rna.22757 | doi-access = free | url = https://zenodo.org/records/895827/files/article.pdf }}</ref> The SymE-SymR complex is believed to play an important role in recycling damaged [[RNA]] and [[DNA]].<ref name="Kaw07" /> The relationship and corresponding structures of SymE and SymR provide insight into the mechanism of toxicity and overall role in prokaryotic systems.

== Discovery ==
SymR was originally labelled RyjC and is a 77 [[nucleotide|nucleotide (nt)]] RNA with a  [[sigma factor|σ<sup>70</sup>]] promoter. RyjC was found to overlap the ''yjiW'' [[open reading frame]] on the opposite strand by 6 nt, and was characterized as an [[antisense RNA]] which bound the [[five prime untranslated region|5' untranslated region]] of ''yjiW''.<ref>{{cite journal | vauthors = Kawano M, Reynolds AA, Miranda-Rios J, Storz G | title = Detection of 5'- and 3'-UTR-derived small RNAs and cis-encoded antisense RNAs in Escherichia coli | journal = Nucleic Acids Research | volume = 33 | issue = 3 | pages = 1040–50 | year = 2005 | pmid = 15718303 | pmc = 549416 | doi = 10.1093/nar/gki256 }}</ref> Further study led to the renaming of both ''yjiW'' and RyjC to SymE (SOS-induced yjiW gene with similarity to [https://www.uniprot.org/uniprot/P0AE72 MazE]) and SymR, respectively.<ref name="Kaw07" /> Despite similarities to the AbrB superfamily, the SymE family has been exclusively found in proteobacteria.<ref name="Kaw07" /> 

== Relationship between SymE and SymR ==
The SymR [[antisense RNA]] is [[Transcription (biology)|transcribed]] 3 nt behind the SymE [[start codon]] which is why the SymR promoter is considered embedded within the SymE [[Genetic code|codon]].<ref name=":0" /> As a result, SymR blocks [[RNA]] [[translation (genetics)|translation]] of SymE by antisense binding, suggesting that this ultimately leads to SymR mRNA degradation.<ref name=":7">{{cite journal | vauthors = Fozo EM, Hemm MR, Storz G | title = Small toxic proteins and the antisense RNAs that repress them | journal = Microbiology and Molecular Biology Reviews | volume = 72 | issue = 4 | pages = 579–89, Table of Contents | date = December 2008 | pmid = 19052321 | pmc = 2593563 | doi = 10.1128/MMBR.00025-08 }}</ref> [[Amino acid]] analysis has concluded that SymE may have evolved into an RNA cleavage protein that exhibits toxin-like behavior due to [[Transcription factor|transcription factors]] or [[Antitoxin|antitoxins]].<ref name=":0" /> In contrast to other common toxin-antitoxin systems, the SymR antitoxin is more stable than the SymE toxin.<ref name="Kaw07" /> 

Following [[DNA damage]], the [[SOS response]] represses [[transcription (genetics)|transcription]] of SymR RNA, allowing SymE toxin to degrade potentially damaged mRNA until DNA has been [[DNA repair|repaired]].<ref name="Kaw07" /> Conversely, SymE is tightly repressed by [[Repressor lexA|LexA]] repressor binding sites, SymR, and the [[Lon protease family|Lon protease]].<ref name=":0" /> These three factors are present at multiple levels where LexA is involved in transcription [[Downregulation and upregulation|downregulation]], SymR RNA is involved in translation [[Downregulation and upregulation|downregulation]], and Lon protease is involved in protein [[Denaturation (biochemistry)|degradation]].<ref name="Kaw07" /><ref name=":0" /> The extent of repression on SymE is dependent on the additive power of LexA, SymR, and Lon protease.<ref name=":0" /> Overall, SymE synthesis is slow since its activity is highly dependent on DNA repair proteins.<ref name=":0" /> In the cellular environment, [[mitomycin C]] damages DNA which leads to an overexpression of SymE mRNA to initiate DNA repair.<ref name=":6">{{cite journal | vauthors = Brielle R, Pinel-Marie ML, Felden B | title = Linking bacterial type I toxins with their actions | journal = Current Opinion in Microbiology | volume = 30 | pages = 114–121 | date = April 2016 | pmid = 26874964 | doi = 10.1016/j.mib.2016.01.009 | series = Cell regulation | url = https://www.hal.inserm.fr/inserm-01274292/file/Linking%20bacterial%20type%20I%20toxins%20with%20their%20actions_accepted.pdf }}</ref>

== Toxicity ==
The [[overexpression]] of SymE demonstrated negative effects on the growth of [[Colony-forming unit|colony-forming cells]] when tested ''[[in vitro]]''.<ref name="Kaw07" /> SymE exhibits its [[toxic]]ity by repressing global translation within the [[cell (biology)|cell]], cleaving [[mRNA]] in a similar manner to [https://www.uniprot.org/uniprot/P0AE70 MazF], another toxin.<ref name="Ger07">{{cite journal | vauthors = Gerdes K, Wagner EG | title = RNA antitoxins | journal = Current Opinion in Microbiology | volume = 10 | issue = 2 | pages = 117–24 | date = April 2007 | pmid = 17376733 | doi = 10.1016/j.mib.2007.03.003 }}</ref> Quantitative [[Northern blot]] experiments showed that SymR RNA is present in cells at 10 times the concentration of SymE mRNA (0.02 [[mole (unit)|fmol]] [[Microgram|μg]]<sup>−1</sup> and 0.2 fmol μg<sup>−1</sup>).<ref name="Kaw07" />   

== Structure ==

=== SymE ===
The SymE toxin consists of 113 [[Amino acid|amino acids]].<ref name=":6" /> When evaluating the [[Protein primary structure|amino acid sequence]] and [[Biomolecular structure|tertiary structure]] of SymE, strong similarities were found which resemble the [https://pfam.xfam.org/clan/AbrB AbrB] superfamily.<ref name="Kaw07" /> This superfamily mainly functions as [[Transcription factor|transcription factors]] or [[Antitoxin|antitoxins]]; however, the similarity of SymE to the [[Biomolecular structure|primary sequence]] and [[Protein tertiary structure|tertiary structure]] of the AbrB superfamily suggests that SymE proteins experienced an [[Evolution|evolutionary]] shift from a [[transcription factor]] or [[antitoxin]] to a RNA-associating protein that exhibits toxin behavior.<ref name="Kaw07" /> Between the AbrB superfamily protein structure and the SymE protein structure, there are several key [[Amino acid|hydrophobic residues]] that are highly conserved in the [[Helix-turn-helix|<math>\alpha</math>-helix]] at the center of the protein as well as the [[Beta sheet|<math>\beta</math> strand]]-1.<ref name="Kaw07" /> Despite these key similarities, SymE exhibits polar residues not found in the general structure of the AbrB superfamily, indicating that these residues may have a role in the SymE RNA cleavage ability.<ref name="Kaw07" />

[https://swissmodel.expasy.org/ SWISS-MODEL] contains more than several experimental structures and theoretical [[Homology (biology)|homology]] models that define certain aspects of the SymE [[Biomolecular structure|primary sequence]] and [[Biomolecular structure|tertiary structure]]. The [[UniProt|UniProtKB]] accession number [https://swissmodel.expasy.org/repository/uniprot/P39394 P39394] indicates the general structure of the SymE toxin in [[Escherichia coli O157:H7|''Escherichia coli'' (strain K12)]].<ref name="Kaw07" /><ref>{{Cite web|title=UniProtKB - P39394 (SYME_ECOLI)|url=https://www.uniprot.org/uniprot/P39394|last=The UniProt Consortium|date=2020|website=uniprot.org|url-status=live|archive-url=https://www.uniprot.org/uniprot/P39394?version=*|archive-date=10 July 2007|access-date=4 May 2020}}</ref> In the SWISS-MODEL SymE theoretical model, the [[Alpha helix|<math>\alpha</math>-helix]] contains amino acids [[Glycine|G]]44, [[Glutamine|Q]]45, [[Tryptophan|W]]46, [[Leucine|L]]47, [[Glutamic acid|E]]48, [[Alanine|A]]49, and [[Alanine|A]]50.<ref name=":1">{{cite journal | vauthors = Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TA, Rempfer C, Bordoli L, Lepore R, Schwede T | display-authors = 6 | title = SWISS-MODEL: homology modelling of protein structures and complexes | journal = Nucleic Acids Research | volume = 46 | issue = W1 | pages = W296–W303 | date = July 2018 | pmid = 29788355 | pmc = 6030848 | doi = 10.1093/nar/gky427 }}</ref><ref name=":2">{{cite journal | vauthors = Guex N, Peitsch MC, Schwede T | title = Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective | journal = Electrophoresis | volume = 30 Suppl 1 | issue = S1 | pages = S162-73 | date = June 2009 | pmid = 19517507 | doi = 10.1002/elps.200900140 | s2cid = 39507113 }}</ref><ref name=":3">{{cite journal | vauthors = Bienert S, Waterhouse A, de Beer TA, Tauriello G, Studer G, Bordoli L, Schwede T | title = The SWISS-MODEL Repository-new features and functionality | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D313–D319 | date = January 2017 | pmid = 27899672 | pmc = 5210589 | doi = 10.1093/nar/gkw1132 }}</ref><ref name=":4">{{cite journal | vauthors = Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J, Schwede T | title = QMEANDisCo-distance constraints applied on model quality estimation | journal = Bioinformatics | volume = 36 | issue = 8 | pages = 2647 | date = April 2020 | pmid = 32048708 | pmc = 7178391 | doi = 10.1093/bioinformatics/btaa058 }}</ref><ref name=":5">{{cite journal | vauthors = Bertoni M, Kiefer F, Biasini M, Bordoli L, Schwede T | title = Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 10480 | date = September 2017 | pmid = 28874689 | pmc = 5585393 | doi = 10.1038/s41598-017-09654-8 | bibcode = 2017NatSR...710480B }}</ref> The [[Beta sheet|<math>\beta</math> strand]]-1 contains amino acids [[Glycine|G]]55, [[Threonine|T]]56, [[Alanine|A]]57, [[Valine|V]]58, [[Aspartic acid|D]]59, [[Valine|V]]60, [[Lysine|K]]61, [[Valine|V]]62, [[Isoleucine|I]]67, [[Valine|V]]68, [[Leucine|L]]69, [[Threonine|T]]70, [[Alanine|A]]71, [[Glutamine|Q]]72, [[Proline|P]]73, and [[Proline|P]]74 with the [[Beta turn|<math>\beta</math>-turn]] containing [[Methionine|M]]63, [[Glutamic acid|E]]64, [[Glycine|G]]65, and [[Cysteine|C]]66.<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" />

=== SymR ===
SymR is an [[antisense RNA]] meaning its [[Biomolecular structure|secondary structure]] has characteristic [[Stem-loop|stem-and-loop]] elements as well as unpaired regions flanking the structure.<ref>{{cite book | first1 = Sydney X | last1 = Brenner | first2 = Jeffrey H | last2 = Miller | name-list-style = vanc |title=Encyclopedia of genetics |isbn=0-12-227080-0|location=San Diego|oclc=48655705}}</ref> The predicted [[Biomolecular structure|secondary structure]] of SymR showcases a loop containing the nucleotide sequence CCAG.<ref name=":7" /> This characteristic loop is shared with the lstR-1 and OhsC RNA proteins and is predicted to be a [[binding site]] for other proteins.<ref name=":7" /> Currently, there are no known files on the [https://www.rcsb.org/ RCSB protein data bank] or [https://swissmodel.expasy.org/repository SWISS-MODEL repository] that indicate a predicted tertiary structure of SymR. 

== See also ==
* [[Toxin-antitoxin system]]
* [[Hok/sok system]]

== References ==
{{reflist|30em}}

== Further reading ==
{{refbegin|30em}}
* {{cite journal | vauthors = Buts L, Lah J, Dao-Thi MH, Wyns L, Loris R | title = Toxin-antitoxin modules as bacterial metabolic stress managers | journal = Trends in Biochemical Sciences | volume = 30 | issue = 12 | pages = 672–9 | date = December 2005 | pmid = 16257530 | doi = 10.1016/j.tibs.2005.10.004 }}
* {{cite journal | vauthors = Gerdes K, Christensen SK, Løbner-Olesen A | title = Prokaryotic toxin-antitoxin stress response loci | journal = Nature Reviews. Microbiology | volume = 3 | issue = 5 | pages = 371–82 | date = May 2005 | pmid = 15864262 | doi = 10.1038/nrmicro1147 | s2cid = 13417307 }}
* {{cite journal | vauthors = Lewis LK, Harlow GR, Gregg-Jolly LA, Mount DW | title = Identification of high affinity binding sites for LexA which define new DNA damage-inducible genes in Escherichia coli | journal = Journal of Molecular Biology | volume = 241 | issue = 4 | pages = 507–23 | date = August 1994 | pmid = 8057377 | doi = 10.1006/jmbi.1994.1528 }}
* {{cite journal | vauthors = Christensen SK, Pedersen K, Hansen FG, Gerdes K | title = Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA | journal = Journal of Molecular Biology | volume = 332 | issue = 4 | pages = 809–19 | date = September 2003 | pmid = 12972253 | doi = 10.1016/S0022-2836(03)00922-7 }}
* {{cite journal | vauthors = Engelberg-Kulka H, Glaser G | title = Addiction modules and programmed cell death and antideath in bacterial cultures | journal = Annual Review of Microbiology | volume = 53 | pages = 43–70 | year = 1999 | pmid = 10547685 | doi = 10.1146/annurev.micro.53.1.43 }}
* {{cite journal | vauthors = Cherepanov PP, Wackernagel W | title = Gene disruption in Escherichia coli: TcR and KmR cassettes with the option of Flp-catalyzed excision of the antibiotic-resistance determinant | journal = Gene | volume = 158 | issue = 1 | pages = 9–14 | date = May 1995 | pmid = 7789817 | doi = 10.1016/0378-1119(95)00193-A }}
* {{cite journal | vauthors = Anantharaman V, Aravind L | title = New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system | journal = Genome Biology | volume = 4 | issue = 12 | pages = R81 | year = 2003 | pmid = 14659018 | pmc = 329420 | doi = 10.1186/gb-2003-4-12-r81 | doi-access = free }}
{{refend}}

== External links ==
* {{Rfam|id=RF01809|name=SymR antitoxin}}

[[Category:Antisense RNA]]
[[Category:RNA antitoxins]]