1. Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina 27709, USA
2. Graduate School of Frontier Biosciences, Osaka University and CREST, Japan Science and Technology Corporation, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan
3. Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
4. Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Correspondence to: Thomas A. Kunkel¹ Email: kunkel@niehs.nih.gov

Abstract

Human DNA polymerase (Pol ) 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 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 to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol 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 sequences^{4, 5, 6}. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol during dimer bypass could contribute to mutagenesis and skin cancer.

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