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

EMBO Rep. 2011 Feb;12(2):164-71. doi: 10.1038/embor.2010.195. Epub 2011 Jan 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Biological Evolution
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Cross-Linking Reagents / toxicity
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Etoposide / toxicity
  • Female
  • Gene Knockdown Techniques
  • Methyl Methanesulfonate / toxicity
  • Mice / embryology
  • Mitomycin / toxicity
  • Muscle Development / drug effects*
  • Mutagens / toxicity*
  • MyoD Protein / genetics
  • MyoD Protein / metabolism*
  • Myogenic Regulatory Factor 5 / genetics
  • Myogenic Regulatory Factor 5 / metabolism*
  • Phosphorylation
  • Pregnancy
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-abl / physiology
  • RNA Interference
  • Somites / drug effects
  • Somites / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Cross-Linking Reagents
  • DNA-Binding Proteins
  • Mutagens
  • Myf5 protein, mouse
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myogenic Regulatory Factor 5
  • Tumor Suppressor Proteins
  • Mitomycin
  • Etoposide
  • Methyl Methanesulfonate
  • Proto-Oncogene Proteins c-abl
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases