Radiosensitization of yeast cells by inhibition of histone h4 acetylation.
Deletion of genes for proteins involved in histone H4 acetylation produces sensitivity to DNA-damaging agents in both Saccharomyces cerevisiae and mammalian cells. In the present studies, we show that treating wild-type yeast cells with histone acetyl transferase (HAT) inhibitors, which are chemicals that cause a global decrease in histone H4 acetylation, sensitizes the cells to ionizing radiation. Using HAT inhibitors, we have placed histone H4 acetylation into the RAD51-mediated homologous recombination repair pathway. We further show that yeast cells with functionally defective HAT proteins have normal phospho-H2A (gamma-H2A) induction after irradiation but a reduced rate of loss of gamma-H2A. This argues that HAT-defective cells are able to detect DNA double-strand breaks normally but have a defect in the repair of these lesions. We also show that cells treated with HAT inhibitors have intact G1 and G2 checkpoints after exposure to ionizing radiation, suggesting that G1 and G2 checkpoint activation is independent of histone H4 acetylation.
Song
Suisui
S
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University of School of Medicine, Stanford, California.
McCann
Kelly E
KE
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University of School of Medicine, Stanford, California.
Brown
J Martin
JM
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University of School of Medicine, Stanford, California.
D000107:Acetylation; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism*; D011836:Radiation Tolerance; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000528:radiation effects*
D004791:Enzyme Inhibitors; D006657:Histones; D051548:Histone Acetyltransferases