Abstract
Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cells, Cultured
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Cisplatin / pharmacology
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DNA Damage*
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DNA Repair
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Etoposide / pharmacology
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Methyl Methanesulfonate / pharmacology
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Mice
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / drug effects
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Mutagens / pharmacology
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MyoD Protein / drug effects
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MyoD Protein / genetics
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MyoD Protein / metabolism
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Myoblasts / cytology
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Myoblasts / drug effects
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Myoblasts / metabolism*
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Myogenin / drug effects
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Myogenin / metabolism
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Myosin Heavy Chains / drug effects
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Myosin Heavy Chains / metabolism
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Phosphorylation
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Point Mutation
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Proto-Oncogene Proteins c-abl / metabolism
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Proto-Oncogene Proteins c-abl / physiology
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Proto-Oncogene Proteins c-jun / physiology
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Radiation, Ionizing
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Transcriptional Activation / drug effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / physiology
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Tyrosine / metabolism
Substances
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Mutagens
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MyoD Protein
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Myog protein, mouse
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Myogenin
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Proto-Oncogene Proteins c-jun
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Tumor Suppressor Protein p53
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Tyrosine
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Etoposide
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Methyl Methanesulfonate
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Proto-Oncogene Proteins c-abl
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Myosin Heavy Chains
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Cisplatin