The genomes of aerobic organisms suffer chronic oxidation of guanine to the genotoxic product 8-oxoguanine (oxoG)1. Replicative DNA polymerases misread oxoG residues and insert adenine instead of cytosine opposite the oxidized base. Both bases in the resulting A·oxoG mispair are mutagenic lesions, and both must undergo base-specific replacement to restore the original C·G pair. Doing so represents a formidable challenge to the DNA repair machinery, because adenine makes up roughly 25% of the bases in most genomes. The evolutionarily conserved enzyme adenine DNA glycosylase (called MutY in bacteria and hMYH in humans) initiates repair of A·oxoG to C·G by removing the inappropriately paired adenine base from the DNA backbone. A central issue concerning MutY function is the mechanism by which A·oxoG mispairs are targeted among the vast excess of A·T pairs. Here we report the use of disulphide crosslinking2 to obtain high-resolution crystal structures of MutY–DNA lesion-recognition complexes. These structures reveal the basis for recognizing both lesions in the A·oxoG pair and for catalysing removal of the adenine base.
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We thank H. Nash for the reduced abasic phosphoramidite; Y. Korkhin for assistance with data collection and processing; M. Becker for beamline assistance; S. Bruner and J. J. Miranda for critically reading the manuscript; and Enanta Pharmaceuticals for use of their X-ray generator and detector. Some data for this study were measured at beamline X25 of the National Synchrotron Light Source; financial support for this beamline comes from the NIH and the United States Department of Energy.
The authors declare that they have no competing financial interests.
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Fromme, J., Banerjee, A., Huang, S. et al. Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature 427, 652–656 (2004). https://doi.org/10.1038/nature02306
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