Oxidative DNA damage and OGG1 at the crossroad between DNA repair and transcriptional regulation – OxiREPTRA

By limiting the impact of DNA damage, DNA repair systems play a critical role in cell survival and the avoidance of mutations leading to pathologies such as neurodegenerative diseases, cancer, and accelerated aging. We have recently shown that in response to oxidative stress, the co-transcriptional regulator Mediator complex is essential for the chromatin recruitment of OGG1, the DNA glycosylase that initiates base excision repair (BER) of the mutagenic 8-oxoG lesion. During the last few years, a new exciting view has emerged suggesting that 8-oxoG is not only a DNA lesion that challenges the stability of our genomes but could also be considered an epigenetic mark playing a major role in transcriptional activation. Most of our knowledge regarding the mechanisms underlying the search and cleavage of 8-oxoG by OGG1 comes from in vitro experiments on 8-oxoG containing naked DNA but very little is known about the impact of the chromatin state on these processes. Our project aims to fill this gap by assessing directly in living cells and at the single molecule resolution the dynamic behavior of OGG1 and the Mediator complex upon oxidative stress. Our findings will shed light on the complex interplay between repair and transcription, two processes that appear to be intimately connected according to an ever-growing number of evidences. Assessing the search strategies employed by OGG1 to detect 8-oxoG lesions within the nucleus will also bring new concepts beyond the DNA repair field by showing how proteins navigate within the highly complex nuclear environment and find their target with high efficiency and specificity.