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How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome? Ostiane D’Augustin, Sébastien Huet, Anna Campalans, Juan Pablo Radicella

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How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome? Ostiane D’Augustin, Sébastien Huet, Anna Campalans, Juan Pablo Radicella Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome? Ostiane D’augustin, Sébastien Huet, Anna Campalans, Juan Pablo Radicella To cite this version: Ostiane D’augustin, Sébastien Huet, Anna Campalans, Juan Pablo Radicella. Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome?. International Journal of Molecular Sciences, MDPI, 2020, 21 (21), 10.3390/ijms21218360. hal- 03007117 HAL Id: hal-03007117 https://hal.archives-ouvertes.fr/hal-03007117 Submitted on 16 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License International Journal of Molecular Sciences Review Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome? Ostiane D’Augustin 1,2 ,Sébastien Huet 2,3,* , Anna Campalans 1,* and Juan Pablo Radicella 1,* 1 Institute of Cellular and Molecular Radiobiology, Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Université de Paris, 18 route du Panorama, F-92265 Fontenay-aux-Roses, France; [email protected] 2 Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR 6290, BIOSIT-UMS3480, F-35000 Rennes, France 3 Institut Universitaire de France, F-75000 Paris, France * Correspondence: [email protected] (S.H.); [email protected] (A.C.); [email protected] (J.P.R.) Received: 30 September 2020; Accepted: 4 November 2020; Published: 7 November 2020 Abstract: The most frequent DNA lesion resulting from an oxidative stress is 7,8-dihydro-8-oxoguanine (8-oxoG). 8-oxoG is a premutagenic base modification due to its capacity to pair with adenine. Thus, the repair of 8-oxoG is critical for the preservation of the genetic information. Nowadays, 8-oxoG is also considered as an oxidative stress-sensor with a putative role in transcription regulation. In mammalian cells, the modified base is excised by the 8-oxoguanine DNA glycosylase (OGG1), initiating the base excision repair (BER) pathway. OGG1 confronts the massive challenge that is finding rare occurrences of 8-oxoG among a million-fold excess of normal guanines. Here, we review the current knowledge on the search and discrimination mechanisms employed by OGG1 to find its substrate in the genome. While there is considerable data from in vitro experiments, much less is known on how OGG1 is recruited to chromatin and scans the genome within the cellular nucleus. Based on what is known of the strategies used by proteins searching for rare genomic targets, we discuss the possible scenarios allowing the efficient detection of 8-oxoG by OGG1. Keywords: OGG1; 8-oxoG; DNA repair; base excision repair; search mechanism 1. 8-Oxoguanine: Biological Relevance and Repair 1.1. Biological Prominence and Consequences of 8-Oxoguanine Reactive oxygen species (ROS) arise within the cell as a consequence of the cellular metabolism as well as of the exposure to environmental factors. While ROS are required for the normal functioning of the cell, an intracellular excess of ROS leads to oxidative stress resulting in the abnormal oxidation of biological macromolecules. In the case of DNA, ROS can induce a plethora of chemical modifications, including strand breaks and oxidized bases. Amongst the latter, 7,8-dihydro-8-oxoguanine (8-oxoG), an oxidized form of guanine, is the most abundant [1,2]. Indeed, in human cells 8-oxoG is present at a steady state level of two to three residues per 106 guanines [3,4]. Its predominance is likely due to guanine having the lowest oxidative potential among all DNA (and RNA) bases [5,6]. Guanine can be oxidized directly or upon electron transfer from one base to another over distances up to 37 Å due to π-stacking interactions between the bases, the 50-G of a 50-GG-30 doublet being the most likely to be oxidized [7]. Int. J. Mol. Sci. 2020, 21, 8360; doi:10.3390/ijms21218360 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci.Sci. 20202020,,21 21,, 8360x FOR PEER REVIEW 22 of of 18 18 Accumulation of oxidative base damage in genomic DNA and deficiency in its repair, have been associatedAccumulation with several of oxidative pathologies base damage and ageing in genomic [8,9]. DNAWhile and these deficiency effects inmostly its repair, originate have beenfrom associatedmutations with consecutive several pathologies to base oxidation, and ageing 8-oxoG [8,9]. While was these also effreportedects mostly to originateinterfere fromwith mutations telomere consecutivereplication toleading base oxidation, to genomic 8-oxoG instability was also reportedand ageing-related to interfere withdiseases telomere [10–14]. replication Oxidation leading of tomitochondrial genomic instability DNA has and also ageing-related been implicated diseases in ne [10urodegenerative–14]. Oxidation diseases of mitochondrial and ageing. DNA Confirming has also beenthe deleterious implicated consequences in neurodegenerative of 8-oxoG diseases accumulation and ageing. in DNA, Confirming mutations the affecting deleterious the consequences genes coding offor 8-oxoG the enzymes accumulation involved in DNA,in the mutationsrepair of this affecting lesion thearegenes linked coding to several for the human enzymes diseases involved [15]. in the repair8-oxoG of this lesiononly differs are linked from to normal several guanine human diseases by two [atoms:15]. C8 and N7, harbouring an oxygen instead8-oxoG of a onlyhydrogen, differs and from a normal hydrogen guanine instead by twoof an atoms: electron C8 pair, andN7, respectively harbouring (Figure an oxygen 1a). While instead 8- ofoxoG a hydrogen, affects the and thermodynamic a hydrogen instead stability of anof electronthe duplex pair, [16,17], respectively structural (Figure studies1a). showed While 8-oxoG that its apresenceffects the induces thermodynamic little or stabilityno distortion of the of duplex the DNA [16,17 helix,], structural yielding studies a normal showed Watson–Crick that its presence base- inducesparing arrangement little or no distortion[18–20]. As ofa consequence, the DNA helix, 8-ox yieldingoG does not a normal block DNA Watson–Crick replication, base-paring although it arrangementmay decrease [18 the–20 ].rateAs of a consequence,DNA synthesis 8-oxoG or induce does pausing not block of DNA the polymerase replication, [21]. although Nor itdoes may it decreaseconstitute the a ratepermanent of DNA barrier synthesis to tr oranscription induce pausing [22]. Yet, of the the polymerase capacity of [8-oxoG21]. Nor to does form it a constitute Hoogsteen a permanentbase pair with barrier an toadenine transcription through [22 an]. anti-syn Yet, the capacityconformation of 8-oxoG (Figure to form 1b) [19,23] a Hoogsteen leads to base the pair frequent with anincorporation adenine through of adenine an anti-syn oppositeconformation to 8-oxoG during (Figure DNA1b) [ synthesis19,23] leads [24,25]. to the Up frequenton further incorporation replication, ofa G:C adenine to T:A opposite transversion to 8-oxoG is fixed, during making DNA of synthesis 8-oxoG [a24 highly,25]. Upon pre-mu furthertagenic replication, lesion [26] a (Figure G:C to T:A 1c). transversionSimilarly, the is 8-oxoG:A fixed, making Hoogsteen of 8-oxoG base a pair highly can pre-mutagenic occur during transcription, lesion [26] (Figure resulting1c). Similarly,in mutant theRNAs 8-oxoG:A [27]. Hoogsteen base pair can occur during transcription, resulting in mutant RNAs [27]. FigureFigure 1. 1.8-oxoG 8-oxoG is is a premutagenica premutagenic lesion. lesion. (a )( 8-oxoGa) 8-oxoG and and G. DiG.ff Differenceserences are representedare represented in red. in (bred.) G:C, (b) 8-oxoG:CG:C, 8-oxoG:C and 8-oxoG:A and 8-oxoG:A base pairs. base pairs. (c) Fixation (c) Fixation of a transversion of a transversion due to du thee to presence the presence of 8-oxoG. of 8-oxoG. 1.2. 8-oxoG Repair in Mammalian Cells 1.2. 8-oxoG Repair in Mammalian Cells In cells, the removal of non-canonical or damaged bases from DNA is achieved mainly by the In cells, the removal of non-canonical or damaged bases from DNA is achieved mainly by the base excision repair (BER) pathway. This pathway has been extensively reviewed over time [28–30]. base excision repair (BER) pathway. This pathway has been extensively reviewed over time [28–30]. The initial step in the repair is the recognition of the modified base and cleavage of the N-glycosydic The initial step in the repair is the recognition of the modified base and cleavage of the N-glycosydic bond by a specific DNA glycosylase to generate an abasic (AP) site. The AP site is processed by the bond by a specific DNA glycosylase to generate an abasic (AP) site. The AP site is processed by the downstream enzymes of the pathway. downstream enzymes of the pathway. Int. J. Mol. Sci. 2020, 21, 8360 3 of 18 The discovery and characterization of the yeast 8-oxoG DNA glycosylase [31,32] allowed the identification of the mammalian orthologue (OGG1) [33–39]. Like the yeast enzyme, mammalian OGG1 has a strong preference for the excision of 8-oxoG paired to a cytosine, rather than to other bases. Cleavage of the 8-oxoG N-glycosydic bond by OGG1 leaves an AP site. While OGG1 can act in vitro as a bifunctional DNA glycosylase, the β-elimination cleavage of the AP site seems to be uncoupled from the DNA glycosylase activity [40–42].
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