| STRUCTURE |
The process by which cells correct the damage done to DNA by reactive oxygen species just got a little clearer, thanks to a new structure of the repair enzyme MutY bound to its damaged substrate. Produced by everything from smoking to normal metabolic activity, reactive oxygen species are constantly damaging the nucleotide bases that make up genomic DNA. One of the most common types of damage is the conversion of guanine to 8-oxoguanine (8-oxoG). If allowed to persist, 8-oxoG lesions will pair with adenine--not cytosine, guanine's normal partner--during DNA replication. CUT IT OUT The repair enzyme MutY (gray) bends the DNA helix (gold) while searching for adenine residues that are mispaired with the damaged base 8-oxoguanine (yellow). To fix such mismatches, MutY extrudes the adenine (red) into its active site and clips the base from the DNA backbone. Other enzymes then pitch in to restore the original DNA sequence. COURTESY OF CHRIS FROMME/HARVARD UNIVERSITY 8-OxoG:A mispairs eventually give rise to dangerous genetic mutations, so cells have devised a way to repair both bases to restore the original DNA sequence. MutY carries out the first step of this process: finding 8-oxoG:A mispairs and removing the adenine. "How MutY distinguishes A residues paired abnormally with 8-oxoG amidst the vast excess of A residues paired normally with T [thymine] has been a long-standing question in the field," notes Harvard University chemistry professor Gregory L. Verdine. Verdine, graduate student J. Christopher Fromme, and their coworkers have now neatly answered this question by solving a 2.2-Å X-ray structure of MutY bound to DNA containing an 8-oxoG:A mispair [Nature, 427, 652 (2004)]. None of the half dozen hydrogen bonds that the enzyme makes to the 8-oxoG in this structure would be possible with a thymine, Verdine points out. The structure also reveals how MutY removes the unwanted adenine. MutY creates a sharp bend in the DNA at the site of the 8-oxoG:A mispair. It then extrudes the adenine into its active site and clips the base from the DNA backbone |
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