DNA damage-activated ABL-MyoD signaling contributes to DNA repair in skeletal myoblasts.
Previous works have established a unique function of MyoD in the control of muscle gene expression during DNA damage response in myoblasts. Phosphorylation by DNA damage-activated ABL tyrosine kinase transiently inhibits MyoD-dependent activation of transcription in response to genotoxic stress. We show here that ABL-MyoD signaling is also an essential component of the DNA repair machinery in myoblasts exposed to genotoxic stress. DNA damage promoted the recruitment of MyoD to phosphorylated Nbs1 (pNbs1)-containing repair foci, and this effect was abrogated by either ABL knockdown or the ABL kinase inhibitor imatinib. Upon DNA damage, MyoD and pNbs1 were detected on the chromatin to MyoD target genes without activating transcription. DNA damage-mediated tyrosine phosphorylation was required for MyoD recruitment to target genes, as the ABL phosphorylation-resistant MyoD mutant (MyoD Y30F) failed to bind the chromatin following DNA damage, while retaining the ability to activate transcription in response to differentiation signals. Moreover, MyoD Y30F exhibited an impaired ability to promote repair in a heterologous system, as compared with MyoD wild type (WT). Consistently, MyoD-null satellite cells (SCs) displayed impaired DNA repair that was rescued by reintroduction of MyoD WT but not by MyoD Y30F. In addition, inhibition of ABL kinase prevented MyoD WT-mediated rescue of DNA repair in MyoD-null SCs. These results identify an unprecedented contribution of MyoD to DNA repair and suggest that ABL-MyoD signaling coordinates DNA repair and transcription in myoblasts.
1] Epigenetics and Regenerative Medicine, IRCCS Fondazione Santa Lucia, Rome, Italy [2] Muscle Development and Regeneration, Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
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Simonatto
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Chiacchiera
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Musaró
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D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D017570:MyoD Protein / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D016196:S Phase; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D002843:Chromatin; D017570:MyoD Protein; D016315:Proto-Oncogene Proteins c-abl