title: BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways.
abstract: The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. A previously suggested mechanism for this regulation consists of the ability of Tip60 to coactivate transcription by the tumor suppressor p53. In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia-related substrates. In contrast, p53 was not required for UV-induced DDR. Rather, p53 accumulation by either knockdown of Mdm2 or addition of an Mdm2 inhibitor, Nutlin-3, before irradiation strongly attenuated the UV-induced DDR and increased cell survival. This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. We conclude that Tip60 enables UV-induced DDR signaling even in the absence of p53, whereas preaccumulated p53 suppresses UV-induced DDR by reducing the levels of BRCA1.
authors.affiliation: Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, 5000 Odense C, Denmark.
authors.forename: Dominique
authors.initials: D
authors.lastname: Kranz
authors.forename: Christoph
authors.initials: C
authors.lastname: Dohmesen
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000528:radiation effects; D000074443:Lysine Acetyltransferase 5; D008954:Models, Biological; D009153:Mutagens; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D051716:Replication Protein A / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D009153:Mutagens; D010879:Piperazines; D034741:RNA, Small Interfering; D051716:Replication Protein A; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases