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

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.

8-oxoguanine DNA glycosylase1 recognizes oxidatively-generated epitranscriptomic marks on nascent mRNAs to promote RSV replication

“…As a "reader" OGG1 facilitates M2-1 binding to 5'-UTR, thereby promoting mRNA synthesis. Of note, OGG1 has an innate ability to migrate/diffuse along nucleic acid strands without energy requirement 38 . Thus, OGG1 may migrate along with M2-1 on vRNA to facilitate transcription elongation.…”

“…Our results show that RSV infection-induced ROS co-transcriptionally generated 8-oxo(r)Gua in the 5'-UTRs of nascent vRNAs while paired with the 3'-end of genes. 8-oxoguanine DNA glycosylase1 (OGG1), an oxidized Gua base specific DNA repair protein 32,38 , physically interacted with 8-oxo(r)Gua in vRNAs and recruited the RSV-encoded transcription elongation factor M2-1 to promote mRNA synthesis. Knockdown of OGG1 (but not other repair proteins) or inhibition of OGG1 binding to the oxidatively modified Gua(s) decreased viral mRNA, protein levels as well as yield of RSV progeny (100 to 1000-fold) in both airways and cultured cells.…”

New Methodologies to Study DNA Repair Processes in Space and Time Within Living Cells

“…It is this dense and complex structure that needs to be constantly scanned by the DNA repair machinery to detect the presence of DNA lesions. This detection is performed by proteins that can sense specific DNA lesions, such as the DNA-glycosylase OGG1 which detects the oxidized form of guanine ( D’Augustin et al, 2020 ) or the Ku complex which binds to DNA ends consecutive to DSBs ( Ma et al, 2020 ). Nevertheless, each sensor faces a paradox: it needs to scan the DNA quickly, to allow a rapid detection of rare lesions, but also needs to be highly specific, which requires a careful and potentially lengthy inspection of the DNA to avoid missing a lesion or initiating illegitimate repair.…”

“…This key step is ensured by sets of actors that each fulfill a specific function. For example, in the context of base excision repair, the damaged base is first excised by a dedicated glycosylase ( D’Augustin et al, 2020 ). This leaves an abasic site that is itself processed by the endonuclease APE1, generating a single-strand break that is then resolved by the combined action of specific DNA polymerases and ligases ( Abbotts and Wilson, 2017 ).…”

“…This finding asks the question of the strategies used by the repair factors to find their target and reconcile the two opposite requirements of an efficient search process: being fast and specific. Multiple in vitro data on naked DNA demonstrate that repair proteins perform facilitated diffusion to optimize this search process, alternating between 3D exploration phases and 1D diffusion along the DNA ( D’Augustin et al, 2020 ). Nevertheless, it is unclear whether this also holds true when the DNA is wrapped around nucleosomes and folds in the complex multiscale architecture observed in cell nuclei.…”