Programmed DNA damage in myogenesis
Connolly, Patrick F.
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Skeletal muscle is a major tissue type in humans, comprising approximately 40% of total body mass in adults. Skeletal muscle is ultimately composed of elongated multinucleate cells known as myofibers. These myofibers are formed through the differentiation and cell fusion of individual myoblast cells. This process of myogenic fusion is the basis of muscle development in utero, and of muscle regeneration. Myogenic fusion requires the activity of caspases, the proteolytic effectors of apoptotic cell death. One outcome of this myogenic caspase activity is the generation of genomic DNA strand breaks. This occurs through the activity of the endonuclease CAD (caspase-activated DNase). The function of these DNA strand breaks in the context of myogenic differentiation is still unknown. I hypothesize that the role of these strand breaks is to activate elements of the myogenic genetic program by way of the DNA damage response, perhaps through kinase-mediated activation of myogenic transcription factors. Here, I show that artificially-induced DNA strand breaks produced by an exogenous source are sufficient to induce the differentiation of myoblasts in vitro. I also show that a key DNA damage response kinase, DNA-PK, is required for the myogenic differentiation program. This is in line with the theory that DNA damage response factors are involved in propagating the myogenic signal. Furthermore, I show that inhibition of several cell cycle checkpoint kinases induces spontaneous myogenic differentiation, accompanied by massive genomic DNA strand breakage, again suggesting that DNA strand breakage is sufficient to induce differentiation.