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

摘要

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). Here we have determined the efficiency and fidelity of dimer bypass. We show that Pol ηcopies 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 ηbypasses 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 sequences. Thus, in normal people and particularly in individuals with NER-defective xeroderma pig-mentosum who accumulate dimers, errors made by Pol η during dimer bypass could contribute to mutagenesis and skin cancer.