Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation.
Acetylation is a prominent post-translational modification of nucleosomal histone N-terminal tails, which regulates chromatin accessibility. Accordingly, histone acetyltransferases (HATs) play major roles in processes such as transcription. Here, we show that the HAT Tip60, which is involved in DNA repair and apoptosis following gamma irradiation, is subjected to proteasome-dependent proteolysis. Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation. Moreover, a ubiquitin ligase-defective mutant of Mdm2 had no effect on Tip60 stability. Our results indicate that Mdm2 targets both p53 and Tip60, suggesting that these two proteins could be co-regulated with respect to protein stability. Consistent with this hypothesis, Tip60 levels increased significantly upon UV irradiation of Jurkat cells. Collectively, our results suggest that degradation of Tip60 could be part of the mechanism leading to cell transformation by Mdm2.
Legube
Gaëlle
G
Laboratoire de Biologie Moléculaire Eucaryote, CNRS UMR 5099, 118 Route de Narbonne, Université Paul Sabatier, 31062 Toulouse, France.
Linares
Laetitia K
LK
Lemercier
Claudie
C
Scheffner
Martin
M
Khochbin
Saadi
S
Trouche
Didier
D
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D003546:Cysteine Endopeptidases; D015870:Gene Expression; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D008025:Ligases / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014466:Ultraviolet Rays
D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases