Editing Protein splicing (section)

==History==
The first intein was discovered in 1988 through sequence comparison between the ''[[Neurospora crassa]]''<ref>{{cite journal | last1=Bowman | first1=EJ | last2=Tenney | first2=K | last3=Bowman | first3=BJ | date=Oct 1988 | title=Isolation of genes encoding the Neurospora vacuolar ATPase. Analysis of vma-1 encoding the 67-kDa subunit reveals homology to other ATPases | journal=J Biol Chem | volume=263 | issue=28| pages=13994–4001 | doi=10.1016/S0021-9258(18)68175-X | pmid=2971651 | doi-access=free }}</ref> and carrot<ref>{{cite journal | last1=Zimniak | first1=L | last2=Dittrich | first2=P | last3=Gogarten | first3=JP | last4=Kibak | first4=H | last5=Taiz | first5=L | date=Jul 1988 | title=The cDNA sequence of the 69-kDa subunit of the carrot vacuolar H+-ATPase. Homology to the beta-chain of F0F1-ATPases | journal=J Biol Chem | volume=263 | issue=19| pages=9102–12 | doi=10.1016/S0021-9258(19)76514-4 | pmid=2897965 | doi-access=free }}</ref> [[vacuole|vacuolar]] [[ATPase]] (without intein) and the [[homology (biology)|homologous]] gene in yeast (with intein) that was first described as a putative [[ion transporter|calcium ion transporter]].<ref>{{cite journal | last1=Shih | first1=CK | last2=Wagner | first2=R | last3=Feinstein | first3=S | last4=Kanik-Ennulat | first4=C | last5=Neff | first5=N | date=Aug 1988 | title=A dominant trifluoperazine resistance gene from Saccharomyces cerevisiae has homology with F0F1 ATP synthase and confers calcium-sensitive growth | journal=Mol Cell Biol | volume=8 | issue=8| pages=3094–103 | pmc=363536 | pmid=2905423 | doi=10.1128/mcb.8.8.3094}}</ref> In 1990 Hirata ''et al.''<ref>{{cite journal | last1=Hirata | first1=R | last2=Ohsumk | first2=Y | last3=Nakano | first3=A | last4=Kawasaki | first4=H | last5=Suzuki | first5=K | last6=Anraku | first6=Y | date=Apr 1990 | title=Molecular structure of a gene, VMA1, encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae | journal=J Biol Chem | volume=265 | issue=12| pages=6726–33 | doi=10.1016/S0021-9258(19)39210-5 | pmid=2139027 | doi-access=free }}</ref> demonstrated that the extra sequence in the yeast gene was transcribed into mRNA and removed itself from the host protein only after translation. Since then, inteins have been found in all [[Three-domain system|three domains of life]] (eukaryotes, bacteria, and archaea) and in [[virus]]es.

Protein splicing was unanticipated and its mechanisms were discovered by two groups (Anraku <ref>{{cite journal |vauthors=Hirata R, Ohsumk Y, Nakano A, Kawasaki H, Suzuki K, Anraku Y |title=Molecular structure of a gene, VMA1, encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae |journal=J. Biol. Chem. |volume=265 |issue=12 |pages=6726–33 |date=April 1990 |doi=10.1016/S0021-9258(19)39210-5 |pmid=2139027 |doi-access=free }}</ref> and Stevens<ref>{{cite journal |vauthors=Kane PM, Yamashiro CT, Wolczyk DF, Neff N, Goebl M, Stevens TH |title=Protein splicing converts the yeast TFP1 gene product to the 69-kD subunit of the vacuolar H(+)-adenosine triphosphatase |journal=Science |volume=250 |issue=4981 |pages=651–7 |date=November 1990 |pmid=2146742 |doi= 10.1126/science.2146742|bibcode=1990Sci...250..651K }}</ref>) in 1990. They both discovered a ''[[Saccharomyces cerevisiae]]'' VMA1 in a precursor of a [[vacuolar ATPase|vacuolar H<sup>+</sup>-ATPase]] enzyme. The amino acid sequence of the N- and C-termini corresponded to 70% DNA sequence of that of a vacuolar H<sup>+</sup>-ATPase from other organisms, while the amino acid sequence of the central position corresponded to 30% of the total DNA sequence of the [[yeast]] HO [[nuclease]].

Many [[gene]]s have unrelated intein-coding segments inserted at different positions. For these and other reasons, inteins (or more properly, the gene segments coding for inteins) are sometimes called ''[[selfish genetic elements]]'', but it may be more accurate to call them [[Parasite|parasitic]]. According to the gene centered view of evolution, most genes are "selfish" only insofar as to compete with other genes or [[allele]]s but usually they fulfill a function for the organisms, whereas "parasitic genetic elements", at least initially, do not make a positive contribution to the fitness of the organism.<ref name="SwithersSoucy2012">{{cite journal| last1=Swithers| first1=Kristen S.| last2=Soucy| first2=Shannon M.| last3=Gogarten| first3=J. Peter| title=The Role of Reticulate Evolution in Creating Innovation and Complexity| journal=International Journal of Evolutionary Biology| volume=2012| year=2012| pages=1–10| issn=2090-8032| doi=10.1155/2012/418964| pmid=22844638| pmc=3403396| doi-access=free}}</ref><ref>{{cite book | last=Dawkins | first=Richard| author-link=Richard Dawkins | title=[[The Selfish Gene]] | year=1976 | publisher=Oxford University Press}}</ref>

As of December 2019, the UniProtKB database contains 188 entries manually annotated as inteins, ranging from just tens of amino acid residues to thousands.<ref>{{Cite journal |date=2016-11-29 |title=UniProt: the universal protein knowledgebase |url=http://dx.doi.org/10.1093/nar/gkw1099 |journal=Nucleic Acids Research |volume=45 |issue=D1 |pages=D158–D169 |doi=10.1093/nar/gkw1099 |pmid=27899622 |pmc=5210571 |issn=0305-1048}}</ref> The first intein was found encoded within the VMA gene of ''Saccharomyces cerevisiae''. They were later found in fungi ([[ascomycetes]], [[basidiomycetes]], [[zygomycetes]] and [[chytrids]]) and in diverse proteins as well. A protein distantly related to known inteins containing protein, but closely related to metazoan [[hedgehog protein]]s, has been described to have the intein sequence from [[Glomeromycota]]. Many of the newly described inteins contain homing endonucleases and some of these are apparently active.<ref name="Perler2002">{{cite journal| last1=Perler| first1=F. B.| title=InBase: the Intein Database| journal=Nucleic Acids Research| volume=30| issue=1| year=2002| pages=383–384| issn=1362-4962| doi=10.1093/nar/30.1.383| pmid=11752343| pmc=99080}}</ref> The abundance of intein in fungi indicates [[Horizontal gene transfer|lateral transfer]] of intein-containing genes. While in eubacteria and archaea, there are 289 and 182 currently known inteins. Not surprisingly, most intein in eubacteria and archaea are found to be inserted into nucleic acid metabolic protein, like fungi.<ref name="Perler2002" />

Inteins vary greatly, but many of the same intein-containing proteins are found in a number of species. For example, pre-mRNA processing factor 8 ([[Prp8]]) protein, instrumental in the [[spliceosome]], has seven different intein insertion sites across eukaryotic species.<ref>{{Cite journal |last1=Green |first1=Cathleen M. |last2=Li |first2=Zhong |last3=Smith |first3=Aaron D. |last4=Novikova |first4=Olga |last5=Bacot-Davis |first5=Valjean R. |last6=Gao |first6=Fengshan |last7=Hu |first7=Saiyang |last8=Banavali |first8=Nilesh K. |last9=Thiele |first9=Dennis J. |last10=Li |first10=Hongmin |last11=Belfort |first11=Marlene |date=2019-10-10 |title=Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing |journal=PLOS Biology |language=en |volume=17 |issue=10 |pages=e3000104 |doi=10.1371/journal.pbio.3000104 |issn=1545-7885 |pmc=6805012 |pmid=31600193 |doi-access=free }}</ref> Intein-containing Prp8 is most commonly found in fungi, but is also seen in [[Amoebozoa]], [[Chlorophyta]], [[Capsaspora]], and [[Choanoflagellida]]. Many mycobacteria contain inteins within [[dnaB helicase|DnaB]] (bacterial replicative helicase), [[RecA]] (bacterial DNA recombinase), and SufB ([[Iron–sulfur cluster biosynthesis|FeS cluster assembly]] protein).<ref name=":0"/><ref name="Wall 2021">{{Cite journal |last1=Wall |first1=Diana A. |last2=Tarrant |first2=Seanan P. |last3=Wang |first3=Chunyu |last4=Mills |first4=Kenneth V. |last5=Lennon |first5=Christopher W. |date=2021 |title=Intein Inhibitors as Novel Antimicrobials: Protein Splicing in Human Pathogens, Screening Methods, and Off-Target Considerations |journal=Frontiers in Molecular Biosciences |volume=8 |page=752824 |doi=10.3389/fmolb.2021.752824 |issn=2296-889X |pmc=8529194 |pmid=34692773 |doi-access=free }}</ref> There is remarkable variety within the structure and number of DnaB inteins, both within the mycobacterium genus and beyond. Interestingly, intein-containing DnaB is also found in the [[chloroplast]]s of algae.<ref>{{Cite journal |last1=Green |first1=Cathleen M. |last2=Novikova |first2=Olga |last3=Belfort |first3=Marlene |date=2018-01-24 |title=The dynamic intein landscape of eukaryotes |journal=Mobile DNA |volume=9 |issue=1 |pages=4 |doi=10.1186/s13100-018-0111-x |issn=1759-8753 |pmc=5784728 |pmid=29416568 |doi-access=free }}</ref> Intein-containing proteins found in archaea include RadA (RecA homolog), RFC, PolB, RNR.<ref name="Novikova 14490–14497">{{Cite journal |last1=Novikova |first1=Olga |last2=Topilina |first2=Natalya |last3=Belfort |first3=Marlene |date=May 2014 |title=Enigmatic Distribution, Evolution, and Function of Inteins |journal=Journal of Biological Chemistry |volume=289 |issue=21 |pages=14490–14497 |doi=10.1074/jbc.r114.548255 |issn=0021-9258 |pmc=4031506 |pmid=24695741 |doi-access=free }}</ref> Many of the same intein-containing proteins (or their homologs) are found in two or even all three domains of life. Inteins are also seen in the proteomes encoded by bacteriophages and eukaryotic viruses. Viruses may have been involved as vectors of intein distribution across the wide variety of intein containing organisms.<ref name="Novikova 14490–14497"/>