Tyteca Sandrine, Vandromme Marie, Legube Gaëlle, Chevillard-Briet Martine, Trouche Didier
Laboratoire de Biologie Moléculaire Eucaryote (LBME), UMR 5099 CNRS/Université Paul Sabatier, Institut d'Exploration Fonctionnelle des Génomes (IEFG), Toulouse, France.
EMBO J. 2006 Apr 19;25(8):1680-9. doi: 10.1038/sj.emboj.7601066. Epub 2006 Apr 6.
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.
组蛋白乙酰转移酶Tip60（HTATIP）属于一种多分子复合物，参与细胞对DNA损伤的反应。Tip60通过使p53激活p21CIP（p21）表达，参与DNA损伤后的细胞周期阻滞。我们在此表明，Tip60以及属于Tip60复合物的E1A相关p400蛋白（EP400）对于DNA损伤诱导的凋亡也是必需的。Tip60最有可能通过刺激p53的DNA结合活性来促进一些促凋亡p53靶基因的表达。相反，p400在未受应激的细胞中抑制p21表达，从而允许细胞周期进程和DNA损伤诱导的凋亡。因此，在没有DNA损伤的情况下，Tip60和p400对p21表达具有相反的作用。我们进一步发现，这种拮抗作用依赖于p400对Tip60功能的抑制，这种特性在DNA损伤后会被消除。因此，综合来看，我们的结果表明Tip60和p400在DNA损伤诱导的凋亡中发挥不同作用，并强调了Tip60复合物及其调控在正确控制细胞命运中的重要性。
