Mutagenic conformation of 8-oxo-7,8-dihydro-2′-dGTP in the confines of a DNA polymerase active site

Laboratory of Structural Biology, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 07/2010; 17(7):889-90. DOI: 10.1038/nsmb.1852
Source: PubMed


The major product of oxidative base damage is 8-oxo-7,8-dihydro-2'-deoxyguanine (8odG). The coding potential of this lesion is modulated by its glycosidic torsion angle that controls whether its Watson-Crick or Hoogsteen edge is used for base pairing. The 2.0-A structure of DNA polymerase (pol) beta bound with 8odGTP opposite template adenine indicates that the modified nucleotide assumes the mutagenic syn conformation and that the nonmutagenic anti conformation would be incompatible with efficient DNA synthesis.

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Available from: Rajendra Prasad
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    • "The oxidized nucleotide 8-oxo-dGTP has also dual base-pairing properties, although an intramolecular hydrogen bond between N2 of 8-oxo-dGTP and a non-bridging oxygen on the α-phosphate might strongly favour the syn conformation (29). Moreover, incorporation of 8-oxo-dGTP in the anti conformation seems to be unfavoured due to the steric repulsion between O8 and its sugar-phosphate backbone and also between O8 and the sugar (C2’) of the primer ‘terminus’ (29). Consequently, most DNA polymerases prefer to insert 8-oxo-dGTP opposite a template dA. "
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    • "Thus, even with the 160-fold concentration advantage of 8-oxo-dGTP relative to dGTP employed in the mutagenesis procedure, the incorporation of 8-oxo-dGTP likely was disfavored at C positions. The recently reported crystal structure of 8-oxo-dGTP bound opposite dA in the active site DNA polymerase β confirms the substantially more favorable geometry of this pairing compared to that of 8-oxo-dGTP and dC (19). dPTP, in contrast, gave rise to A-to-G and G-to-A transition mutations in a symmetrical manner, occurring at a frequency of 1.7 and 1.6%, respectively. "
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