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Review
. 2020 Nov 7;21(21):8360.
doi: 10.3390/ijms21218360.

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 , Juan Pablo Radicella  1
Affiliations
Review

Lost in the Crowd: How Does Human 8-Oxoguanine DNA Glycosylase 1 (OGG1) Find 8-Oxoguanine in the Genome?

Ostiane D'Augustin et al. Int J Mol Sci. .

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: 8-oxoG; DNA repair; OGG1; base excision repair; search mechanism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
8-oxoG is a premutagenic lesion. (a) 8-oxoG and G. Differences are represented in red. (b) G:C, 8-oxoG:C and 8-oxoG:A base pairs. (c) Fixation of a transversion due to the presence of 8-oxoG.
Figure 2
Figure 2
Proposed OGG1 diffusion modes.
Figure 3
Figure 3
Induction of 8-oxoG and recruitment of OGG1-GFP to chromatin. (a) Exposure of cells to KBrO3 results in a global induction of 8-oxoG in the nuclear genome leading to recruitment of OGG1 to chromatin. Left panel: 8-oxoG was detected using a specific antibody against the lesion (green) and DNA was stained with PI (red). Right panel: The fusion of OGG1 to the fluorescent protein GFP (green), allows following the distribution of the protein in untreated cells or cells exposed to KBrO3. The soluble fraction was extracted before imaging to detect the association of the protein with chromatin. Nuclear DNA was stained with DAPI (blue). Scale bars: 5 μm. (b) Recruitment of OGG1-GFP to 8-oxoG induced by laser micro-irradiation. Left panel: The antibody against 8-oxoG (magenta) reveals the formation of the lesion at the same regions where OGG1-GFP (green) was recruited. Right panel: Recruitment of OGG1-GFP in real time by live-cell imaging. Scale bars: 5 μm.
Figure 4
Figure 4
Compact versus non-compact exploration modes in target search.
See this image and copyright information in PMC

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