ING5 Is a Tip60 Cofactor That Acetylates p53 in Response to DNA Damage

Posttranslational modification of p53 is a critical event in regulating the expression of its target genes. p53 is acetylated at lysine 120 (K120) by acetyltranferases Tip60 (KAT5) and hMOF (KAT8) in response to DNA damage. Identification of cofactors for these two enzymes will shed light on the mechanism by which cells make a choice between cell-cycle arrest and apoptosis. It has been reported that ING5, a member of the inhibitor of growth (ING) family, is involved in p53-dependent pathways, but its exact role is unknown. In this study, we found that ING5 expression was significantly increased and that ING5 assisted Tip60, but not hMOF, in acetylating p53 at K120 in response to DNA damage. ING5 had no effect on acetylation of p53 at K373/382, but it formed a complex with p53 and Tip60. ING5 was required for acetylation of p53 at K120, and p53 acetylated at K120 subsequently bound to the promoters of its target apoptotic genes, BAX and GADD45, to promote their expression and lead to apoptosis. Mutation of K120 to K120R abolished the effects of ING5 on p53-induced gene expression. Thus, we conclude that ING5 functions as a cofactor of Tip60 in the acetylation of p53 at K120 in response to DNA damage. (c) 2013 AACR.