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An evolutionarily acquired genotoxic response discriminates MyoD from Myf5, and differentially regulates hypaxial and epaxial myogenesis

Despite having distinct expression patterns and phenotypes in mutant mice, the myogenic regulatory factors Myf5 and MyoD have been considered to be functionally equivalent. Here, we report that these factors have a different response to DNA damage, due to the presence in MyoD and absence in Myf5 of...

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Published in:EMBO reports 2011-02, Vol.12 (2), p.164-171
Main Authors: Innocenzi, Anna, Latella, Lucia, Messina, Graziella, Simonatto, Marta, Marullo, Fabrizia, Berghella, Libera, Poizat, Coralie, Shu, Chih-Wen, Wang, Jean Y J, Puri, Pier Lorenzo, Cossu, Giulio
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Language:English
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Summary:Despite having distinct expression patterns and phenotypes in mutant mice, the myogenic regulatory factors Myf5 and MyoD have been considered to be functionally equivalent. Here, we report that these factors have a different response to DNA damage, due to the presence in MyoD and absence in Myf5 of a consensus site for Abl ‐mediated tyrosine phosphorylation that inhibits MyoD activity in response to DNA damage. Genotoxins failed to repress skeletal myogenesis in MyoD ‐null embryos; reintroduction of wild‐type MyoD , but not mutant Abl phosphorylation‐resistant MyoD , restored the DNA‐damage‐dependent inhibition of muscle differentiation. Conversely, introduction of the Abl‐responsive phosphorylation motif converts Myf5 into a DNA‐damage‐sensitive transcription factor. Gene‐dosage‐dependent reduction of Abl kinase activity in MyoD‐expressing cells attenuated the DNA‐damage‐dependent inhibition of myogenesis. The presence of a DNA‐damage‐responsive phosphorylation motif in vertebrate, but not in invertebrate MyoD suggests an evolved response to environmental stress, originated from basic helix–loop–helix gene duplication in vertebrate myogenesis. Skeletal myogenesis in mammals is spatially divided into an epaxial, Myf5‐dependent and a hypaxial, MyoD‐dependent compartment. It is shown here that genotoxins inhibit MyoD‐, but not Myf5‐dependent differentiation, through Abl‐mediated phosphorylation of a site that is present in MyoD, but not in Myf5. Swapping this site converts MyoD into a genotoxin‐resistant and Myf5 into a genotoxin‐sensitive factor. This difference might be related to the evolution of hypaxial myogenesis.
ISSN:1469-221X
1469-3178
DOI:10.1038/embor.2010.195