Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

It has been suggested that the oxidtaive DNA base lesion 8-oxo-7,8-dihydroguanine (OG) and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA- sequencing to correlate genome-wide distribution of OG with gene transcription in HAP1 cells deficient for OGG1 and/or MUTYH. Our data identified moderate enrichment of OG in the genome that is mainly driven by the genomic context and not affected by DNA glycosylase-initiated repairs. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that it functions as a sensor of cellular stress to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.