MutY adenine DNA glycosylase/DNA lesion in A*oxoG pair complex
Bacillus stearothermophilus (bacteria)
Aerobic organisms generate energy from ATP with the help of oxygen. Their genes, in particular guanine bases, are therefore oxidized easily. Oxidized guanine, 8-oxoguanine (oxoG) is a genotoxic product. Replicative DNA polymerases misread oxoG and insert adenine instead of cytosine opposite to the oxidized base of oxoG. Both bases of the adenine-oxoG mismatch pair are mutagenic DNA lesions and considered one of the causes for cancers and aging. Therefore they have to undergo DNA-repair such as the replacement of the mismatch pair with a cytosine-guanine pair. The DNA-repair machinery involves the following steps; an adenine base of the adenine-oxoG mismatch pair is removed through the catalytic action of adenine DNA glycosylases, generating an abasic site. Then repair polymerases replace a cytosine with the abasic site. The resulting cytosine-oxoG pair undergoes removal of oxoG by 8-oxoguanine DNA glycosylases, and a guanine is inserted through the catalysis of repair polymerases. Thus a biologically functional C-G pair is restored.
The structure of a complex of adenine DNA glycosylase, MutY, with double stranded DNA has been determined. MutY finds adenine-oxoG mismatch pairs and removes the adenine base of this pair. This enzyme has a catalytic domain constructed of two modules, a [4Fe-4S] cluster and a six-helix barrel module, and provides a deep pocket for the substrate, formed at the junction of the two modules. The C-terminal domain of MutY contacts the oxoG-side strand, but interacts with the MutY catalytic domain as well. This interdomain contact allows MutY to encircle the DNA duplex. The adenine base of adenine-oxoG protrudes from the DNA helix and therefore readily fits into the pocket in the MutY catalytic domain. Subsequently the adenine base is removed. In this way MutY recognizes adenine-oxoG lesions and removes the adenine base.
Protein Data Bank (PDB)
Fromme, J.C. Banerjee, A. Huang, S.J. Verdine, G.L.; "Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase"; Nature; (2004) 427:652-656 PubMed:14961129.
author: Yuko Tsuchiya