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bioRxiv · 10.1101/2022.06.23.497315

DNA-PKcs regulates myogenesis in an AKT-dependent manner independent of induced DNA damage

Sutcu, H. H.·Ricchetti, M.
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Abstract

Skeletal muscle regeneration relies on muscle stem (satellite) cells. We previously demonstrated that satellite cells efficiently and accurately repair radiation-induced DNA double-strand breaks (DSBs) via the DNA-dependent kinase DNA-PKcs. We show here that DNA-PKcs affects myogenesis independently of its role in DSB repair. Consequently, this process does not require the accumulation of DSBs and it is also independent of caspase-induced DNA damage. We report that in myogenic cells DNA-PKcs is essential for the expression of the differentiation factor Myogenin in an Akt2-dependent manner. DNA-PKcs interacts with the p300-containing complex that activates Myogenin transcription. We show also that SCID mice that are deficient in DNA-PKcs, and are used for transplantation and muscle regeneration studies, display altered myofiber composition and delayed myogenesis upon injury. These defects are exacerbated after repeated injury/regeneration events resulting in reduced muscle size. We thus identify a novel regulator of myogenic differentiation, and define a differentiation phase that does not involve the DNA damage/repair process.

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Sutcu, H. H., Ricchetti, M.. 2022-06-23. DNA-PKcs regulates myogenesis in an AKT-dependent manner independent of induced DNA damage. https://doi.org/10.1101/2022.06.23.497315

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