Identification of key residues of the DNA glycosylase OGG1 controlling efficient DNA sampling and recruitment to oxidized bases in living cells

Ostiane D’augustin (1, 2) , Virginie Gaudon (3) , Capucine Siberchicot (1) , Rebecca Smith (4, 5) , Catherine Chapuis (4) , Jordane Depagne (1) , Xavier Veaute (1, 6) , Didier Busso (1, 6) , Anne-Marie Di Guilmi (7) , Bertrand Castaing (3) , J Pablo Radicella (8) , Anna Campalans , Sébastien Huet (4)

1 SGCSR (U_1274 / UMR_E_008) - Stabilité génétique, cellules souches et radiations
2 SFR UMS CNRS 3480 - INSERM 018 - Biosit : biologie, santé, innovation technologique
3 CBM - Centre de biophysique moléculaire
4 IGDR - Institut de Génétique et Développement de Rennes
5 Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes
6 CEA, IBFJ, IRCM - Commissariat à l'Energie Atomique, Institut de Radiobiologie Cellulaire et Moléculaire
7 JACOB - Institut de Biologie François JACOB
8 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire

Abstract The DNA-glycosylase OGG1 oversees the detection and clearance of the 7,8-dihydro-8-oxoguanine (8-oxoG), which is the most frequent form of oxidized base in the genome. This lesion is deeply buried within the double-helix and its detection requires careful inspection of the bases by OGG1 via a mechanism that remains only partially understood. By analyzing OGG1 dynamics in the nucleus of living human cells, we demonstrate that the glycosylase constantly samples the DNA by rapidly alternating between diffusion within the nucleoplasm and short transits on the DNA. This sampling process, that we find to be tightly regulated by the conserved residue G245, is crucial for the rapid recruitment of OGG1 at oxidative lesions induced by laser micro-irradiation. Furthermore, we show that residues Y203, N149 and N150, while being all involved in early stages of 8-oxoG probing by OGG1 based on previous structural data, differentially regulate the sampling of the DNA and recruitment to oxidative lesions.

Domaines: Sciences du Vivant [q-bio]

Ostiane D’augustin, Virginie Gaudon, Capucine Siberchicot, Rebecca Smith, Catherine Chapuis, et al.. Identification of key residues of the DNA glycosylase OGG1 controlling efficient DNA sampling and recruitment to oxidized bases in living cells. Nucleic Acids Research, 2023, 51 (10), pp.4942-4958. ⟨10.1093/nar/gkad243⟩. ⟨hal-04088267v1⟩