Preferential cis–syn thymine dimer bypass by DNA polymerase η occurs with biased fidelity

Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide excision repair (NER)1,2. Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol η copies thymine dimers and the flanking bases with higher processivity than it copies undamaged DNA, and then switches to less processive synthesis. This ability of Pol η to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol η bypasses a dimer with low fidelity and with higher error rates at the 3′ thymine than at the 5′ thymine. A similar bias is seen with Sulfolobus solfataricus DNA polymerase 4, which forms a Watson–Crick base pair at the 3′ thymine of a dimer but a Hoogsteen base pair at the 5′ thymine (ref. 3). Ultraviolet-induced mutagenesis is also higher at the 3′ base of dipyrimidine sequences4,5,6. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.