Acetylation of the p53 DNA-binding domain regulates apoptosis induction.
The ability of p53 to induce apoptosis plays an important role in tumor suppression. Here, we describe a previously unknown posttranslational modification of the DNA-binding domain of p53. This modification, acetylation of lysine 120 (K120), occurs rapidly after DNA damage and is catalyzed by the MYST family acetyltransferases hMOF and TIP60. Mutation of K120 to arginine, as occurs in human cancer, debilitates K120 acetylation and diminishes p53-mediated apoptosis without affecting cell-cycle arrest. The K120R mutation selectively blocks the transcription of proapoptotic target genes such as BAX and PUMA while the nonapoptotic targets p21 and hMDM2 remain unaffected. Consistent with this, depletion of hMOF and/or TIP60 inhibits the ability of p53 to activate BAX and PUMA transcription. Furthermore, the acetyllysine 120 (acetyl-K120) form of p53 specifically accumulates at proapoptotic target genes. These data suggest that K120 acetylation may help distinguish the cell-cycle arrest and apoptotic functions of p53.
Sykes
Stephen M
SM
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Mellert
Hestia S
HS
Holbert
Marc A
MA
Li
Keqin
K
Marmorstein
Ronen
R
Lane
William S
WS
McMahon
Steven B
SB
D000107:Acetylation; D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001665:Binding Sites; D002453:Cell Cycle; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C496552:KAT8 protein, human; D000074443:Lysine Acetyltransferase 5