Figure 7.

p53-mediated repression of myogenin regulates muscle differentiation in response to genotoxic stress. Muscle differentiation is represented in black lines and p53-mediated regulation in heavy red lines. Skeletal muscle differentiation is orchestrated by members of the MyoD family of transcription factors. MyoD determines the myogenic lineage and acts upstream of p21 and myogenin.^{8, 9, 13, 56} Under normal conditions, expression of both p21 and myogenin is critical to establish the state of irreversible cell cycle arrest and terminal differentiation.^{11, 16, 40} In contrast to the cell cycle arrest that promotes terminal differentiation under non-stressed conditions, it is known that cell cycle arrest induced by DNA damage is associated with decreased myogenic differentiation.²⁶ In addition to the previously characterized mechanism that genotoxic stress inactivates MyoD function through a p53-independent mechanism,^{26, 50, 51, 54} we describe a direct regulatory mechanism by which p53 represses myogenin in response to genotoxic stress. This repression of myogenin leads to reduction of late-stage differentiation and prevents formation of post-mitotic nuclear abnormality in terminally differentiated muscle cells. We propose that the regulation of myogenin plays a critical role not only in driving terminal differentiation but also in maintaining cellular integrity in terminally differentiated muscle cells by virtue of its conditional repression by p53.