Impact and consequences of DNA damageon skeletal muscle cells Haser Hasan SUTCU (1,2*), Miria RICCHETTI (2) and Celine BALDEYRON (1) (1) Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses (2) Institut Pasteur, Team Stability of Nuclear and Mitochondrial DNA, Paris (*) previous address DNA double-strand breaks (DSBs) are dangerous DNA damages and a risk factor for genome stability. The maintenance of genome integrity is crucial for adult stem cells that are responsible for regeneration of damaged tissues and tissue homeostasis throughout life. Skeletal muscle regeneration in the adult relies on muscle stem cells (satellite cells, SCs) that display a remarkable DSB repair activity, but the underlying mechanism is poorly elucidated. In a previous study during my PhD (to be submitted) I investigated the impact of impaired DSB repair on skeletal muscle stem cell viability and differentiation. This work also assessed DSB repair mechanism(s) in muscle stem cells and the consequences on muscle regeneration. This study revealed that DSB repair factors affect myogenesis independently of their DNA repair activity, suggesting that this novel function significantly affects muscle regeneration. In particular, this study addressed the role of DNA-dependent protein kinase (DNA-PK), a crucial factor of non-homologous end-joining (NHEJ), a major pathway involved in DSB repair, in muscle differentiation in the mouse. In my present project at the Institute of Radioprotection and Nuclear Safety (IRSN), we are investigating DNA damage and repair not only in satellite cells but also in post-mitotic, multinucleated muscle fibers (myofibers). Despite that myofibers rarely develop into tumour cells, there has been implications on muscle function upon radiotherapy for other cancer tissues. Accordingly, the present project aims to 1) investigate the consequences of reversible/irreversible DNA damage on nuclei of multi-nucleated fibers, 2) understand radiation-induced DNA damage repair mechanisms in myofibers, and 3) assess the impact of DNA damage on the function and viability of the muscle fibers.
Institut de Radioprotection et de Sûreté Nucléaire (IRSN)
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