Preferential cis-syn thymine dimer bypass by DNA polymerase eta occurs with biased fidelity.
Human DNA polymerase eta (Pol eta) 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 eta 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 eta to sense the dimer location as synthesis proceeds may facilitate polymerase switching before and after lesion bypass. Pol eta 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. Thus, in normal people and particularly in individuals with NER-defective xeroderma pigmentosum who accumulate dimers, errors made by Pol eta during dimer bypass could contribute to mutagenesis and skin cancer.
McCulloch
Scott D
SD
Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina 27709, USA.
Kokoska
Robert J
RJ
Masutani
Chikahide
C
Iwai
Shigenori
S
Hanaoka
Fumio
F
Kunkel
Thomas A
TA
D020029:Base Pairing; D004247:DNA / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D016296:Mutagenesis; D011740:Pyrimidine Dimers / Q000235:genetics / Q000378:metabolism*; D016944:Sulfolobus / Q000201:enzymology; D000099270:Y-Family DNA Polymerases
D004247:DNA; D004259:DNA-Directed DNA Polymerase; D011740:Pyrimidine Dimers; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases