The understanding of the mechanisms of somatic mutation accumulation is essential for cancer research. Sequencing of human cancer genomes led to identification of distinct mutational signatures. However, mutational processes at the origin of many cancers remain poorly understood. Indeed, a wide range of mechanisms from dysfunctions in DNA repair and transcription to exogenous or endogenous mutagen exposures may lead to somatic mutations in cancer genomes. In particular, nucleotide excision repair is coupled with transcription and we recently discovered a novel link between these processes involving Mediator, a conserved multiprotein coactivator.
In this interdisciplinary project, we aim to improve our understanding of the mutational processes at the origin of cancers by deciphering the contribution of transcription and DNA repair combined with mutagen exposure to mutational processes in human cancers, using a combination of genetic, genomic, microfluidic and computational approaches.
Large-scale mutational experiments in human cells being challenging, we will take advantage of the yeast model to identify the most mutagenic combinations of genetic background and mutagen treatment, in relation to transcription, that will be then directly tested in human cells. We will use an innovative microfluidic system to analyse transcription-coupled repair and transcription-associated mutagenesis. A computational analysis of these experimental data will help to understand underlying mechanisms of mutational processes relevant for human cells. We will then transfer the acquired knowledge to human cells by performing mutational experiments in a subset of genetic backgrounds with transcriptional and DNA repair deficiencies treated with mutagens. This work will fill a gap in our understanding of the mutagenesis in relation to transcription and may allow us to propose targets for the development of anticancer therapeutic approaches or modifications of chemotherapeutic treatments.