Tirox

Oxidative DNA damages (OxDD) are the most common DNA damages. These damages include base oxidation, with for example the production of 8-oxoG through guanine oxidation, but also DNA breaks by direct oxidation of the phophodiester DNA backbone. Base oxidation is repaired by the Base Excision Repair (BER) DNA repair process, which involves DNA glycosylases to recognize oxidized bases and whose enzymatic activity creates an abasic site. Abasic sites are cleaved to induce Single Strand Breaks (SSB). Deciphering how transcription is affected by _ and recovers from_ DNA damages is important to fully understand how cells cope with DNA damage. The general objective of our project is to understand the consequence of oxDD and its repair on transcription. It is based on strong preliminary results showing immediate and transient transcriptional changes upon an acute oxidative stress, with hundreds of genes transiently activated or repressed, pointing to major changes in transcription following oxidative damage and efficient recovery mechanisms. More specifically, the aims of our project are (1) to investigate whether transcriptional changes and recovery are due to direct oxDD at genes promoters. (2) to identify transcription-linked processes which are affected by oxDD and (3) to understand the link between oxDD management and transcription-linked processes. To answer these questions, we will make an extensive use of genomics and will take advantage of an original system allowing the targeting of oxDD to chosen regions of the genome. We set up a consortium regrouping three partners with complementary expertise in transcription and chromatin (Partner 1), genomic data analyses (partner 2) and oxDD management (partner 3). At the crossroads between DNA repair and transcription mechanisms, this project falls within the C3 axis “Genetics, Genomics and RNA” of the ANR scientific theme.