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{{Short description|Correction of DNA replication errors}}
The term '''proofreading''' is used in genetics to refer to the error-correcting processes, first proposed by [[John Hopfield]]<ref>{{Cite journal |last=Hopfield |first=J. J. |date=October 1974 |title=Kinetic Proofreading: A New Mechanism for Reducing Errors in Biosynthetic Processes Requiring High Specificity |journal=Proceedings of the National Academy of Sciences |language=en |volume=71 |issue=10 |pages=4135–4139 |doi=10.1073/pnas.71.10.4135 |doi-access=free |issn=0027-8424 |pmc=434344 |pmid=4530290|bibcode=1974PNAS...71.4135H }}</ref> and [[:fr:Jacques Ninio|Jacques Ninio]],<ref>{{Cite journal |last=Ninio |first=Jacques |date=July 1975 |title=Kinetic amplification of enzyme discrimination |url=https://linkinghub.elsevier.com/retrieve/pii/S0300908475801398 |journal=Biochimie |language=en |volume=57 |issue=5 |pages=587–595 |doi=10.1016/S0300-9084(75)80139-8|pmid=1182215 |url-access=subscription }}</ref> involved in [[DNA replication]], [[immune system]] specificity, and enzyme-substrate recognition among many other processes that require enhanced specificity. The [[kinetic proofreading]] mechanisms of Hopfield and Ninio are non-equilibrium active processes that consume ATP to enhance specificity of various biochemical reactions.

In [[bacteria]], all three [[DNA polymerase]]s (I, II and III) have the ability to proofread, using 3' → 5' [[exonuclease]] activity. When an incorrect base pair is recognized, DNA polymerase reverses its direction by one base pair of DNA and excises the mismatched base. Following base excision, the polymerase can re-insert the correct base and replication can continue.

In [[eukaryotes]], only the polymerases that deal with the elongation (delta and epsilon) have proofreading ability (3' → 5' exonuclease activity).<ref>{{Cite journal | doi = 10.1016/j.cell.2007.05.003| title = PCNA, the Maestro of the Replication Fork| journal = Cell| volume = 129| issue = 4| pages = 665–679| year = 2007| last1 = Moldovan | first1 = G. L. | last2 = Pfander | first2 = B. | last3 = Jentsch | first3 = S. | pmid=17512402| s2cid = 3547069| doi-access = free}}</ref>

Proofreading also occurs in [[mRNA translation]] for ''protein'' synthesis.<ref name=Flavio>[http://pharmamotion.com.ar/protein-synthesis-inhibitors-aminoglycosides-mechanism-of-action-animation-classification-of-agents/ Pharmamotion --> Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents] {{webarchive|url=https://web.archive.org/web/20100312134115/http://pharmamotion.com.ar/protein-synthesis-inhibitors-aminoglycosides-mechanism-of-action-animation-classification-of-agents/ |date=2010-03-12 }} Posted by Flavio Guzmán on 12/08/08</ref> In this case, one mechanism is the release of any incorrect [[aminoacyl-tRNA]] before [[peptide bond]] formation.<ref>[http://rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/translate.htm Translation: Protein Synthesis] by Joyce J. Diwan. Rensselaer Polytechnic Institute. Retrieved October 2011 {{Webarchive|url=https://web.archive.org/web/20160307021110/http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/translate.htm |date=2016-03-07 }}</ref>

The extent of proofreading in DNA replication determines the [[mutation rate]], and is different in different species.<ref>{{cite journal|pmid=9560386|pmc=1460098|year=1998|last1=Drake|first1=J. W.|title=Rates of spontaneous mutation|journal=Genetics|volume=148|issue=4|pages=1667–86|last2=Charlesworth|first2=B|last3=Charlesworth|first3=D|last4=Crow|first4=J. F.|doi=10.1093/genetics/148.4.1667}}</ref>
For example, loss of proofreading due to mutations in the [[DNA polymerase epsilon]] gene results in a hyper-mutated genotype with >100 mutations per million bases of DNA in [[Colorectal cancer|human colorectal cancers]].<ref>{{cite journal | journal=Nature | title=Comprehensive molecular characterization of human colon and rectal cancer | year=2012 | author=The Cancer Genome Atlas Network | issue=7407 | pages=330–7 | doi=10.1038/nature11252 | pmid=22810696 | volume=487 | pmc=3401966| last2=Bainbridge | last3=Chang | last4=Dinh | last5=Drummond | last6=Fowler | last7=Kovar | last8=Lewis | last9=Morgan | last10=Newsham | last11=Reid | last12=Santibanez | last13=Shinbrot | last14=Trevino | last15=Wu | last16=Wang | last17=Gunaratne | last18=Donehower | last19=Creighton | last20=Wheeler | last21=Gibbs | last22=Lawrence | last23=Voet | last24=Jing | last25=Cibulskis | last26=Sivachenko | last27=Stojanov | last28=McKenna | last29=Lander | last30=Gabriel | display-authors=29 | bibcode=2012Natur.487..330T }}</ref>

The extent of proofreading in other molecular processes can depend on the [[effective population size]] of the species and the number of genes affected by the same proofreading mechanism.<ref>{{cite journal|vauthors= Rajon E, Masel J | title = Evolution of molecular error rates and the consequences for evolvability| journal = PNAS| year=2011 |volume = 108| issue = 3| pages = 1082–7 |doi=10.1073/pnas.1012918108 | pmid=21199946| pmc = 3024668 | bibcode = 2011PNAS..108.1082R| doi-access = free}}</ref>

==Bacteriophage T4 DNA polymerase==

[[Escherichia virus T4|Bacteriophage (phage) T4]] gene 43 encodes the phage's [[DNA polymerase]] replicative enzyme. [[Temperature-sensitive mutant|Temperature-sensitive (''ts'') gene 43 mutants]] have been identified that have an antimutator [[phenotype]], that is a lower rate of spontaneous [[mutation]] than wild type.<ref>{{cite journal |vauthors=Drake JW, Allen EF |title=Antimutagenic DNA polymerases of bacteriophage T4 |journal=Cold Spring Harb Symp Quant Biol |volume=33 |issue= |pages=339–44 |date=1968 |pmid=5254574 |doi=10.1101/sqb.1968.033.01.039 }}</ref> Studies of one of these mutants, ''tsB120'', showed that the DNA polymerase specified by this mutant copies DNA templates at a slower rate than the wild-type polymerase.<ref name = Gillin1976>{{cite journal |vauthors=Gillin FD, Nossal NG |title=Control of mutation frequency by bacteriophage T4 DNA polymerase. I. The CB120 antimutator DNA polymerase is defective in strand displacement |journal=J Biol Chem |volume=251 |issue=17 |pages=5219–24 |date=September 1976 |doi=10.1016/S0021-9258(17)33149-6 |doi-access=free |pmid=956182 }}</ref> However, the 3' to 5' [[exonuclease]] activity was no higher than wild-type. During [[DNA replication]] the ratio of [[nucleotide]]s turned over to those stably incorporated into newly formed DNA is 10 to 100 times higher in the case of the ''tsB120'' mutant than in wild-type.<ref name = Gillin1976/> It was proposed that the antimutator effect may be explained by both greater accuracy in nucleotide selection and an increased efficiency of removal of noncomplementary nucleotides (proofreading) by the ''tsB120'' polymerase.

When phage T4 virions with a [[wild-type]] gene 43 DNA polymerase are exposed to either [[ultraviolet]] light, which introduces cyclobutane [[pyrimidine dimer]] damages in DNA, or [[psoralen]]-plus-light, which introduces pyrimidine adducts, the rate of mutation increases. However, these mutagenic effects are inhibited when the phage's DNA synthesis is catalyzed by the ''tsCB120'' antimutator polymerase, or another antimutator polymerase, ''tsCB87''.<ref>{{cite journal |vauthors=Yarosh DB, Johns V, Mufti S, Bernstein C, Bernstein H |title=Inhibition of UV and psoralen-plus-light mutagenesis in phage T4 by gene 43 antimutator polymerase alleles |journal=Photochem Photobiol |volume=31 |issue=4 |pages=341–350 |date=April 1980 |pmid=7384228 |doi=10.1111/j.1751-1097.1980.tb02551.x }}</ref> These findings indicate that the level of induction of mutations by DNA damage can be strongly influenced by the gene 43 DNA polymerase proofreading function.

==SARS-CoV-2 proofreading enzyme==

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. The SARS-CoV-2 RNA virus genome encodes a replication-and transcription complex, a multisubunit protein machine that carries out viral genome replication and transcription, processes essential to the virus life cycle. One of the proteins specified by the coronavirus genome is a non-structural protein, nsp14, that is a 3'-to-5' exoribonuclease (ExoN). This protein resides in the protein complex nsp10-nsp14 that enhances replication fidelity by proofreading RNA synthesis, an activity critical for the virus life cycle.<ref>{{cite journal |vauthors=Liu C, Shi W, Becker ST, Schatz DG, Liu B, Yang Y |title=Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme |journal=Science |volume=373 |issue=6559 |pages=1142–6 |date=September 2021 |pmid=34315827 |pmc=9836006 |doi=10.1126/science.abi9310 |bibcode=2021Sci...373.1142L }}</ref> Furthermore, the coronavirus proofreading exoribonuclease nsp14-ExoN is required for maintaining genetic recombination generated during infection.<ref>{{cite journal |vauthors=Gribble J, Stevens LJ, Agostini ML, Anderson-Daniels J, Chappell JD, Lu X, Pruijssers AJ, Routh AL, Denison MR |title=The coronavirus proofreading exoribonuclease mediates extensive viral recombination |journal=PLOS Pathog |volume=17 |issue=1 |article-number=e1009226 |date=January 2021 |pmid=33465137 |pmc=7846108 |doi=10.1371/journal.ppat.1009226 |doi-access=free }}</ref>

== References ==
{{Reflist}}

== External links ==
* [https://web.archive.org/web/20120301075317/http://www.sci.uidaho.edu/bionet/biol115/t6_cell_growth/PDF/T6L2M2_DNA_proofreading_and_repair_transcript.pdf Idaho U. DNA proofreading and repair]
* [https://web.archive.org/web/20120327100733/http://en.scientificcommons.org/55710199 "DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice"]
* {{cite journal |doi=10.1371/journal.pgen.1000060|pmid=18437220|title=Proofreading Activity of DNA Polymerase Pol2 Mediates 3′-End Processing during Nonhomologous End Joining in Yeast|journal=PLOS Genetics|volume=4|issue=4|article-number=e1000060|year=2008|last1=Tseng|first1=Shun-Fu|last2=Gabriel|first2=Abram|last3=Teng|first3=Shu-Chun|pmc=2312331 |doi-access=free }}

[[Category:Biological processes]]
[[Category:DNA replication]]
[[Category:Genetics]]
[[Category:Hydrolases]]
[[Category:DNA repair]]

Proofreading (biology) - История изменений

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