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

Scott D. McCulloch, Robert J. Kokoska, Chikahide Masutani, Shigenori Iwai, Fumio Hanaoka and Thomas A. Kunkel ()
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Scott D. McCulloch: National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park
Robert J. Kokoska: National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park
Chikahide Masutani: Osaka University and CREST, Japan Science and Technology Corporation
Shigenori Iwai: Graduate School of Engineering Science, Osaka University
Fumio Hanaoka: Osaka University and CREST, Japan Science and Technology Corporation
Thomas A. Kunkel: National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park

Nature, 2004, vol. 428, issue 6978, 97-100

Abstract: Abstract 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.

Date: 2004
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DOI: 10.1038/nature02352

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