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During DNA replication, free nucleotides in the cell are added to the new strand in a sequence complementary to the template. Adenine pairs with thymine, and cytosine pairs with guanine.

Sometimes, nucleotides pair incorrectly, such as when adenine pairs with cytosine. DNA polymerase proofreading helps fix these errors and reduces the chance of mutations. If they are not corrected, these errors can cause disease.

First, DNA polymerase binds more strongly to correctly paired nucleotides. This reduces the chance of incorrect pairings.

Second, as nucleotides begin pairing with the template, DNA polymerase undergoes a conformational change. This change causes incorrectly paired nucleotides to detach, allowing the correct nucleotides to be added.

Third, if an incorrect nucleotide is added to the three-prime end of the growing DNA chain, the mismatch distorts the DNA structure and pauses DNA polymerase movement.

DNA polymerase has three-prime-to-five-prime exonuclease activity, which lets it remove an incorrectly added nucleotide. It then inserts the correct nucleotide. This process is called exonucleolytic proofreading.

These steps help keep DNA replication accurate by separating nucleotide selection from error correction.