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

Anna Innocenzi, Lucia Latella, Graziella Messina, Marta Simonatto, Fabrizia Marullo, Libera Berghella, Coralie Poizat, Chih Wen Shu, Jean Y J Wang, Pier Lorenzo Puri, Giulio Cossu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)164-171
Number of pages8
JournalEMBO Reports
Volume12
Issue number2
DOIs
Publication statusPublished - Feb 2011

Keywords

  • cAbl kinase
  • DNA damage
  • Myf5
  • Myo D
  • skeletal myogenesis

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry

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