Repair of oxidative damage to DNA
Sylvie Doublié group (University of Vermont)
The group of Sylvie Doubliť at the University of Vermont
solved structures of two 8-oxoguanine DNA glycosylases, which recognize
specific DNA lesions and initiate repair processes. Guanine is the most
vulnerable of DNA bases to oxidative damage; its most common oxidative
product, 7,8-dihydro-8-oxoguanine (8-oxoG), is the most prevalent defect
found in DNA molecules. In the base-excision DNA repair pathway, 8-oxoG is
recognized by 8-oxoguanine DNA glycoslyase (Ogg), which cleaves the
N-glycosylic bond and then the DNA backbone. Ogg enzymes occur in three
families: Ogg1, Ogg2, and AGOG. This work provides the first Ogg2
structures, from Methanocaldococcus janischii (MjaOgg) and Sulfolobus
solfataricus (SsoOgg). The structures show that the C-terminal lysine of
Ogg2 plays a key role in discriminating between guanine and 8-oxoG in Ogg2.
Comparison with the structure of human Ogg1 shows some conserved features in
the C-terminal region for binding 8-oxoG, as well as some key differences.
Figure: (A) Alignment of the
C-terminal region of several Ogg2 sequences, showing the conserved "stacking"
tryptophan and the C-terminal lysine (red). (B) Ribbon diagram showing a
superposition of the C-terminal loop of MjaOgg (red), SsoOgg (yellow), the
?A-?B loop of human Ogg1 (gray) (PDB 1EBM), and CacOgg (green) (PDB 3F10).
The superposition shows the importance of an aromatic stacking interaction
(Trp198 in Ogg2) with the 8-oxoG substrate.
Faucher, F, Duclos, S, Bandaru, V, Wallace, SS Doublié, S. Crystal
Structures of Two Archaeal 8-Oxoguanine DNA Glycosylases Provide Structural
Insight into Guanine/8-Oxoguanine Distinction, Structure 17 (5), 703-712
(2009). DOI: 10.1016/j.str.2009.03.007