Research Spotlight: Mechanism for Ogg2 DNA glycosylase recognition of the damaged base, 8-oxoguanine
Citation: Faucher F, Wallace SS, and Doublié S. 2010. The C-terminal lysine of Ogg2 DNA glycosylases is a major molecular determinant for guanine/8-oxoguanine distinction. Journal of Molecular Biology 397(1):46-56.
Authors’ Association with MMG:
Frédérick Faucher – was a postdoctoral associate in the MMG Department
Sylvie Doublié – is a Professor in the MMG Department
Susan S. Wallace – is Professor and Chair of the MMG Department
7,8-Dihydro-8-oxoguanine (8-oxoG) is a major oxidative lesion found in DNA. The 8-oxoguanine DNA glycosylases (Ogg) responsible for the removal of 8-oxoG are divided into three families Ogg1, Ogg2 and AGOG. The Ogg2 members are devoid of the recognition loop used by Ogg1 to discriminate between 8-oxoG and guanine and it was unclear until recently how Ogg2 enzymes recognize the oxidized base. We present here the first crystallographic structure of an Ogg2 member, Methanocaldococcus janischii Ogg, in complex with a DNA duplex containing the 8-oxoG lesion. This structure highlights the crucial role of the C-terminal lysine, strictly conserved in Ogg2, in the recognition of 8-oxoG. The structure also reveals that Ogg2 undergoes a conformational change upon DNA binding similar to that observed in Ogg1 glycosylases. Furthermore, this work provides a structural rationale for the lack of opposite base specificity in this family of enzymes.
Impact and Significance:
One of the most abundant oxidative lesions in DNA is 7,8-dihydro-8-oxoguanine (8-oxoG). This damaged base is highly mutagenic because of its ability to form a Hoogsteen pair with adenine (8-oxoG:A), which can lead to a G:C→T:A transversion mutations after replication. Cells have developed mechanisms to repair damaged bases in DNA, one of which is known as the base excision repair (BER) pathway. 8-oxoG is recognized and cleaved by two enzymes of the BER pathway; namely, formamidopyrimidine-DNA glycosylase and 8-oxoguanine DNA glycosylase (Ogg).
The Ogg DNA glycosylases are divided into three structurally distinct families: Ogg1, AGOG and Ogg2, which are mostly found in archaea. Structural work revealed that a recognition loop in the N-terminal domain of Ogg1 is responsible for the discrimination between G and 8-oxoG. Since Ogg2 glycosylases lack this entire domain it was not clear how they could distinguish between the oxidized base and a normal G. A combination of crystallographic and mutagenesis data revealed that the C-terminal lysine of Ogg2 plays a crucial role in the distinction between 8-oxoG and G.