A novel protein with similarities to Rb binding protein 2 compensates for loss of Chk1 function and affects histone modification in fission yeast.
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.
Ahmed
Shakil
S
Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey and Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Palermo
Carmela
C
Wan
Shanhong
S
Walworth
Nancy C
NC
D000107:Acetylation; D020816:Amino Acid Motifs; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009690:Nucleic Acid Conformation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; C486643:Msc1 protein, S pombe; D016160:Retinoblastoma Protein; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605873:Chk1 protein, S pombe; D006655:Histone Deacetylases