Abstract
The conserved protein kinase Chk1 mediates cell cycle progression and consequently the ability of cells to survive when exposed to DNA damaging agents. Cells deficient in Chk1 are hypersensitive to such agents and enter mitosis in the presence of damaged DNA, whereas checkpoint-proficient cells delay mitotic entry to permit time for DNA repair. In a search for proteins that can improve the survival of Chk1-deficient cells exposed to DNA damage, we identified fission yeast Msc1, which is homologous to a mammalian protein that binds to the tumor suppressor Rb (RBP2). Msc1 and RBP2 each possess three PHD fingers, domains commonly found in proteins that influence the structure of chromatin. Msc1 is chromatin associated and coprecipitates a histone deacetylase activity, a property that requires the PHD fingers. Cells lacking Msc1 have a dramatically altered histone acetylation pattern, exhibit a 20-fold increase in global acetylation of histone H3 tails, and are readily killed by trichostatin A, an inhibitor of histone deacetylases. We postulate that Msc1 plays an important role in regulating chromatin structure and that this function modulates the cellular response to DNA damage.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Amino Acid Motifs
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Cycle / physiology
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Cell Nucleus / metabolism
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Checkpoint Kinase 1
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Chromatin / chemistry
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Chromatin / metabolism
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DNA Damage
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Deletion
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism
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Histones / metabolism*
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Humans
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Hydroxamic Acids / metabolism
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Intracellular Signaling Peptides and Proteins*
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Nucleic Acid Conformation
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 2
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Schizosaccharomyces / cytology
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Schizosaccharomyces / genetics
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Schizosaccharomyces / metabolism
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Schizosaccharomyces pombe Proteins / genetics
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Schizosaccharomyces pombe Proteins / metabolism*
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Tumor Suppressor Proteins*
Substances
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Carrier Proteins
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Chromatin
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DNA-Binding Proteins
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Intracellular Signaling Peptides and Proteins
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Msc1 protein, S pombe
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Retinoblastoma Protein
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Schizosaccharomyces pombe Proteins
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Tumor Suppressor Proteins
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trichostatin A
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KDM5A protein, human
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Retinoblastoma-Binding Protein 2
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chk1 protein, S pombe
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Histone Deacetylases