Fidelity, in molecular biology, refers to the accuracy of replication of genetic material, such as DNA or RNA. Replication errors result in mutations that can negatively affect cell viability and health, however, can provide genetic variation to a population.
DNA
To maintain genetic integrity and continuity, DNA polymerases replicate DNA highly accurately. For prokaryotic and eukaryotic cells, DNA is estimated to have one wrong nucleotide incorporated once every 108 to 1010 nucleotides polymerized.[1][2]
Replication errors
Base substitution
A base substitution error, otherwise known as a point mutation, is the result of a misinsertion followed by mismatch extension without proofreading. This can cause three different type of mutations: silent, missense, and nonsense mutations.
The rate of these errors vary from 103-106 nucleotides.[3]
There are two types of these errors: transitions or transversions. These errors depend on the polymerase's selectivity.[2]
Strand misalignment
Strand misalignment errors result in frameshift mutations that can either equal or exceed base substitution rates.[3]
Slippage between the template and primer during replication results in misaligned intermediates. If the unpaired nucleotide is in the template strand, a deletion error occurs. If the unpaired nucleotide is in the primer strand, an insertion error occurs. If a nucleotide is correctly incorporated before further synthesis, realignment occurs that can potentially result in a base substitution.[3]
Mechanisms
Nucleotide selectivity
DNA polymerases are estimated to make an error every 103-106 nucleotides polymerized.[4]
Proofreading
Proofreading improves the fidelity of DNA synthesis by a factor of 102-103. Transition errors are less efficiently proofread than transversion errors.[2]
Mismatch repair
Postreplicative DNA mismatch repair, otherwise known as MMR, repair replication errors that escape proofreading.
RNA
RNA polymerases have mechanisms to select the correct nucleotides, prevent the extension of mismatches, and to excise mismatches after misincorporation.[5]
Effects
Infidelity results in mutations, which in turn, leads to genetic variation within a population. In some cases, when survival is threatened, DNA fidelity decreases to increase the chance of favorable mutations. In Bacterial populations, there are two classes of genes that accelerate genetic variation: stress-inducible wild-type genes and genes that increase genetic variability when they lose their functionality.[6]
See also
References
- Bębenek, Anna; Ziuzia-Graczyk, Izabela (October 2018). "Fidelity of DNA replication-a matter of proofreading". Current Genetics. 64 (5): 985–996. doi:10.1007/s00294-018-0820-1. ISSN 1432-0983. PMC 6153641. PMID 29500597.
- Bębenek, Anna; Ziuzia-Graczyk, Izabela (October 2018). "Fidelity of DNA replication-a matter of proofreading". Current Genetics. 64 (5): 985–996. doi:10.1007/s00294-018-0820-1. ISSN 1432-0983. PMC 6153641. PMID 29500597.
- Kunkel, Thomas A.; Bebenek, Katarzyna (July 2000). "DNA Replication Fidelity". Annual Review of Biochemistry. 69 (1): 497–529. Bibcode:2000ARBio..69..497K. doi:10.1146/annurev.biochem.69.1.497. ISSN 0066-4154. PMID 10966467.
- Showalter, Alexander K.; Tsai, Ming-Daw (2002-08-01). "A Reexamination of the Nucleotide Incorporation Fidelity of DNA Polymerases". Biochemistry. 41 (34): 10571–10576. doi:10.1021/bi026021i. ISSN 0006-2960. PMID 12186540.
- Chung, Claire; Verheijen, Bert M.; Navapanich, Zoe; McGann, Eric G.; Shemtov, Sarah; Lai, Guan-Ju; Arora, Payal; Towheed, Atif; Haroon, Suraiya; Holczbauer, Agnes; Chang, Sharon; Manojlovic, Zarko; Simpson, Stephen; Thomas, Kelley W.; Kaplan, Craig (2023-03-20). "Evolutionary conservation of the fidelity of transcription". Nature Communications. 14 (1): 1547. Bibcode:2023NatCo..14.1547C. doi:10.1038/s41467-023-36525-w. ISSN 2041-1723. PMC 10027832. PMID 36941254.
- Radman, Miroslav (September 2001). "Fidelity and infidelity". Nature. 413 (6852): 115. Bibcode:2001Natur.413..115R. doi:10.1038/35093178. ISSN 1476-4687. PMID 11557959.