Low fidelity DNA synthesis by human DNA polymerase-η

A superfamily of DNA polymerases that bypass lesions in DNA has been described1,2,3,4. Some family members are described as error-prone because mutations that inactivate the polymerase reduce damage-induced mutagenesis. In contrast, mutations in the skin cancer susceptibility gene XPV5,6, which encodes DNA polymerase (pol)-η, lead to increased ultraviolet-induced mutagenesis7,8,9,10,11. This, and the fact that pol-η primarily inserts adenines during efficient bypass of thymine–thymine dimers in vitro8,12,13, has led to the description of pol-η as error-free. However, here we show that human pol-η copies undamaged DNA with much lower fidelity than any other template-dependent DNA polymerase studied. Pol-η lacks an intrinsic proofreading exonuclease activity and, depending on the mismatch, makes one base substitution error for every 18 to 380 nucleotides synthesized. This very low fidelity indicates a relaxed requirement for correct base pairing geometry and indicates that the function of pol-η may be tightly controlled to prevent potentially mutagenic DNA synthesis.