title: Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response.
abstract: Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage-induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. kao@xrt.upenn.edu
authors.forename: Gary D
authors.initials: GD
authors.lastname: Kao
authors.forename: W Gillies
authors.initials: WG
authors.lastname: McKenna
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Guenther
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Yen
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase; D005720:Gamma Rays / Q000009:adverse effects; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C012589:trichostatin A; D005047:Etoposide; C400300:HDAC4 protein, human; D006655:Histone Deacetylases