Tip60 and p400 are both required for UV-induced apoptosis but play antagonistic roles in cell cycle progression.
The histone acetyl transferase Tip60 (HTATIP) belongs to a multimolecular complex involved in the cellular response to DNA damage. Tip60 participates in cell cycle arrest following DNA damage by allowing p53 to activate p21CIP (p21) expression. We show here that Tip60 and the E1A-associated p400 protein (EP400), which belongs to the Tip60 complex, are also required for DNA damage-induced apoptosis. Tip60 favours the expression of some proapoptotic p53 target genes most likely through the stimulation of p53 DNA binding activity. In contrast, p400 represses p21 expression in unstressed cells, thereby allowing cell cycle progression and DNA damage-induced apoptosis. Tip60 and p400 have thus opposite effects on p21 expression in the absence of DNA damage. We further found that this antagonism relies on the inhibition of Tip60 function by p400, a property that is abolished following DNA damage. Therefore, taken together, our results indicate that Tip60 and p400 play distinct roles in DNA damage-induced apoptosis and underline the importance of the Tip60 complex and its regulation in the proper control of cell fate.
Tyteca
Sandrine
S
Laboratoire de Biologie Moléculaire Eucaryote (LBME), UMR 5099 CNRS/Université Paul Sabatier, Institut d'Exploration Fonctionnelle des Génomes (IEFG), Toulouse, France.
Vandromme
Marie
M
Legube
Gaëlle
G
Chevillard-Briet
Martine
M
Trouche
Didier
D
D000074183:ATPases Associated with Diverse Cellular Activities; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002843:Chromatin / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D051548:Histone Acetyltransferases / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
C493956:CDKN1A protein, human; D002352:Carrier Proteins; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C498558:EP400 protein, human; C122079:RUVBL2 protein, human