Structural and functional determinants of the archaeal 8-oxoguanine-DNA glycosylase AGOG for DNA damage recognition and processing

Type Article
Date 2022-10
Language English
Author(s) Coste Franck1, Goffinont Stéphane1, Cros Julien1, Gaudon Virginie1, Guerin Martine1, Garnier Norbert1, Confalonieri FabriceORCID2, Flament DidierORCID3, Suskiewicz Marcin Josef1, Castaing Bertrand1
Affiliation(s) 1 : Centre de Biophysique Moléculaire (CBM), UPR4301 CNRS, Université d’Orléans , CS 80054, rue Charles Sadron , F-45071  Orléans cedex 02 , France
2 : Institut de Biologie Intégrative de la cellule (I2BC), UMR 9198 Université Paris-Saclay-CNRS-CEA , Bâtiment 21, Avenue de la Terrasse , F-91190  Gif-sur-Yvette , France
3 : Université de Brest, Ifremer, CNRS, Unité Biologie et Ecologie des Ecosystèmes marins Profonds (BEEP) , F-29280  Plouzané , France
Source Nucleic Acids Research (0305-1048) (Oxford University Press (OUP)), 2022-10 , Vol. 50 , N. 19 , P. 11072-11092
DOI 10.1093/nar/gkac932
WOS© Times Cited 2

8-Oxoguanine (GO) is a major purine oxidation product in DNA. Because of its highly mutagenic properties, GO absolutely must be eliminated from DNA. To do this, aerobic and anaerobic organisms from the three kingdoms of life have evolved repair mechanisms to prevent its deleterious effect on genetic integrity. The major way to remove GO is the base excision repair pathway, usually initiated by a GO-DNA glycosylase. First identified in bacteria (Fpg) and eukaryotes (OGG1), GO-DNA glycosylases were more recently identified in archaea (OGG2 and AGOG). AGOG is the less documented enzyme and its mode of damage recognition and removing remains to be clarified at the molecular and atomic levels. This study presents a complete structural characterisation of apo AGOGs from Pyrococcus abyssi (Pab) and Thermococcus gammatolerans (Tga) and the first structure of Pab-AGOG bound to lesion-containing single- or double-stranded DNA. By combining X-ray structure analysis, site directed mutagenesis and biochemistry experiments, we identified key amino acid residues of AGOGs responsible for the specific recognition of the lesion and the base opposite the lesion and for catalysis. Moreover, a unique binding mode of GO, involving double base flipping, never observed for any other DNA glycosylases, is revealed. In addition to unravelling the properties of AGOGs, our study, through comparative biochemical and structural analysis, offers new insights into the evolutionary plasticity of DNA glycosylases across all three kingdoms of life.

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Coste Franck, Goffinont Stéphane, Cros Julien, Gaudon Virginie, Guerin Martine, Garnier Norbert, Confalonieri Fabrice, Flament Didier, Suskiewicz Marcin Josef, Castaing Bertrand (2022). Structural and functional determinants of the archaeal 8-oxoguanine-DNA glycosylase AGOG for DNA damage recognition and processing. Nucleic Acids Research, 50(19), 11072-11092. Publisher's official version : , Open Access version :