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Nucleic Acids Res. 2015 Jan;43(2):932-42. doi: 10.1093/nar/gku1353. Epub 2014 Dec 30.

Switching between polymerase and exonuclease sites in DNA polymerase ε.

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Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden.
Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden


The balance between exonuclease and polymerase activities promotes DNA synthesis over degradation when nucleotides are correctly added to the new strand by replicative B-family polymerases. Misincorporations shift the balance toward the exonuclease site, and the balance tips back in favor of DNA synthesis when the incorrect nucleotides have been removed. Most B-family DNA polymerases have an extended β-hairpin loop that appears to be important for switching from the exonuclease site to the polymerase site, a process that affects fidelity of the DNA polymerase. Here, we show that DNA polymerase ε can switch between the polymerase site and exonuclease site in a processive manner despite the absence of an extended β-hairpin loop. K967 and R988 are two conserved amino acids in the palm and thumb domain that interact with bases on the primer strand in the minor groove at positions n-2 and n-4/n-5, respectively. DNA polymerase ε depends on both K967 and R988 to stabilize the 3'-terminus of the DNA within the polymerase site and on R988 to processively switch between the exonuclease and polymerase sites. Based on a structural alignment with DNA polymerase δ, we propose that arginines corresponding to R988 might have a similar function in other B-family polymerases.

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