Fidelity of DNA Replication

DNA replication is, by far, the most accurate of known enzyme-catalyzed processes. The error rate per base pair per round of replication is about 10-9 to 10-10. The accuracy cannot be explained, however, by the different binding energies between correct and incorrect base pairs (this amounts to only a 100 to 1000 fold difference between correct and incorrect pairing).

Two cellular systems aid the fidelity of replication. These include the following:

> 1. The 3'-5' exonuclease activity of DNA polymerases acts as a "proofreading" system. This appears to function based on the slow rate at which incorrectly paired nucleotides are extended by the DNA polymerase. Correctly incorporated nucleotides have subsequent nucleotides put onto them very fast (Figure 24.36). Incorrectly incorporated nucleotides are not readily extended by the polymerase very efficiently, allowing them to be melted away to the 3'-5' exonuclease site of the polymerase for removal (Figure 24.44).

> 2. The mismatch repair system makes an additional contribution to accuracy of about 100-fold. It works by scanning the newly replicated DNA, excising any residues that are not properly base-paired and replacing them with the correct nucleotides.

The role of hydrogen bonding between bases as a fidelity-improving mechanism during polymerization has been brought into question with the fact that a geometric derivative of dTTP is readily incorporated by Klenow fragment of DNA Polymerase I very readily, despite being unable to form hydrogen bonds with dAMP in the template DNA.

See also: E. coli DNA Polymerases, Other Replication Proteins

INTERNET LINK: Mismatch Repair