Proofreading (biology)

The term proofreading is used in genetics to refer to the error-correcting processes, first proposed by John Hopfield and Jacques Ninio, involved in DNA replication, immune system specificity, enzyme-substrate recognition among many other processes that require enhanced specificity. The 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 polymerases (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).[1]

Proofreading also occurs in mRNA translation for protein synthesis.[2] In this case, one mechanism is release of any incorrect aminoacyl-tRNA before peptide bond formation.[3]

The extent of proofreading in DNA replication determines the mutation rate, and is different in different species.[4] For example, loss of proofreading due to mutations in the DNA polymerase epsilon gene results in a hyper-mutated genotype with >100 mutations per Mbase of DNA in human colorectal cancers.[5]

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.[6]

References

  1. ↑ Moldovan, G. L.; Pfander, B.; Jentsch, S. (2007). "PCNA, the Maestro of the Replication Fork". Cell. 129 (4): 665–79. doi:10.1016/j.cell.2007.05.003. PMID 17512402.
  2. ↑ Pharmamotion --> Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents Posted by Flavio Guzmán on 12/08/08
  3. ↑ Translation: Protein Synthesis by Joyce J. Diwan. Rensselaer Polytechnic Institute. Retrieved October 2011
  4. ↑ Drake, J. W.; Charlesworth, B; Charlesworth, D; Crow, J. F. (1998). "Rates of spontaneous mutation". Genetics. 148 (4): 1667–86. PMC 1460098Freely accessible. PMID 9560386.
  5. ↑ The Cancer Genome Atlas Network; Bainbridge; Chang; Dinh; Drummond; Fowler; Kovar; Lewis; Morgan; Newsham; Reid; Santibanez; Shinbrot; Trevino; Wu; Wang; Gunaratne; Donehower; Creighton; Wheeler; Gibbs; Lawrence; Voet; Jing; Cibulskis; Sivachenko; Stojanov; McKenna; Lander; et al. (2012). "Comprehensive molecular characterization of human colon and rectal cancer". Nature. 487 (7407): 330–337. Bibcode:2012Natur.487..330T. doi:10.1038/nature11252. PMC 3401966Freely accessible. PMID 22810696.
  6. ↑ Rajon, E., Masel, J.; Masel (2011). "Evolution of molecular error rates and the consequences for evolvability". PNAS. 108 (3): 1082–1087. Bibcode:2011PNAS..108.1082R. doi:10.1073/pnas.1012918108. PMC 3024668Freely accessible. PMID 21199946.

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