The aim of this project is to improve our understanding of the mutational processes at the origin of cancers by deciphering the contribution of genetic background and mutagen exposure to mutational signatures observed in cancer cells, using a combination of genetic, genomic, microfluidic and computational approaches. More specifically, a novel methodological framework based on microfluidics, allowing to considerably accelerate mutation accumulation experiments in yeast, will be applied to the analysis of transcription-coupled repair and transcription-associated mutagenesis involving Mediator. A computational model will be derived from these experimental data and analysis of available cancer genome sequencing data will be revisited in light of this knowledge