title: Coordination of cell cycle, DNA repair and muscle gene expression in myoblasts exposed to genotoxic stress.
abstract: Upon exposure to genotoxic stress, skeletal muscle progenitors coordinate DNA repair and the activation of the differentiation program through the DNA damage-activated differentiation checkpoint, which holds the transcription of differentiation genes while the DNA is repaired. A conceptual hurdle intrinsic to this process relates to the coordination of DNA repair and muscle-specific gene transcription within specific cell cycle boundaries (cell cycle checkpoints) activated by different types of genotoxins. Here, we show that, in proliferating myoblasts, the inhibition of muscle gene transcription occurs by either a G 1- or G 2-specific differentiation checkpoint. In response to genotoxins that induce G 1 arrest, MyoD binds target genes but is functionally inactivated by a c-Abl-dependent phosphorylation. In contrast, DNA damage-activated G 2 checkpoint relies on the inability of MyoD to bind the chromatin at the G 2 phase of the cell cycle. These results indicate an intimate relationship between DNA damage-activated cell cycle checkpoints and the control of tissue-specific gene expression to allow DNA repair in myoblasts prior to the activation of the differentiation program.
authors.affiliation: Istituto Dulbecco Telethon, IRCCS Fondazione Santa Lucia and European Brain Research Institute, Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Simonatto
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Giordani
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Marullo
authors.forename: Giulia Claudia
authors.initials: GC
authors.lastname: Minetti
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D016193:G1 Phase; D016195:G2 Phase; D005786:Gene Expression Regulation; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D017570:MyoD Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D010766:Phosphorylation; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002843:Chromatin; D017570:MyoD Protein; D016877:Oxidants; D016315:Proto-Oncogene Proteins c-abl