Molecular physio-pathological mechanisms of Mediatorpathies associated to transcription-coupled repair

• Applicant: Professor Dr. Björn Schumacher
• Subject Area: General Genetics and Functional Genome Biology ; Human Genetics ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545378328

Gene expression is associated with DNA repair via specific pathways to ensure the continuity of RNA synthesis and the genome integrity after DNA damage. The Mediator is an essential complex controlling the transcription of most protein-coding genes. Recently, Mediator has been also involved in DNA repair including transcription coupled repair (TCR) but its roles remain elusive. Deregulation of some of these DNA repair pathways and especially TCR can lead to genetic disorders as we recently demonstrated with rare diseases caused by mutations in subunits of the Mediator complex, regrouped as Mediatorpathies. MEDITRAC project aims to (i) Understand the molecular mechanisms on transcription and TCR involving Mediator and the consequences of the identified pathogenic variants and (ii) determine the physiopathological impacts on neurodevelopment of Mediator-related alterations. Our approach using pathogenic mutations in in vitro, yeast, and human neural models supported by the French partners is a powerful system to study DNA repair and transcription. The C. elegans model developed by the German coordinator is a tremendous added-value to decipher the neurodevelopmental consequences of the Mediatorpathies in a metazoan organism. Our consortium is using powerful cutting-edge approaches in functional genomics, genetics, structural biology, physiopathology in combination with clinical research to hopefully translate our fundamental findings into clinical implications linking genetic mutations to clinical features. The experimental pipeline supporting this project will be a valuable tool to be deployed for the study of all Mediatorpathies as well as the rare diseases related to dysregulation of TCR. In addition, the new methodologies developed in MEDITRAC will be applied in diagnosis bringing tools for a precise and relevant functional characterization for these rare diseases.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partners: Nicolas Le May, Ph.D.; Dr. Natacha Rochel; Dr. Julie Soutourina