Stabilization of p21 (Cip1/WAF1) following Tip60-dependent acetylation is required for p21-mediated DNA damage response

M-S Lee; J Seo; D Y Choi; E-W Lee; A Ko; N-C Ha; J Bok Yoon; H-W Lee; K Pyo Kim; J Song

doi:10.1038/cdd.2012.159

Stabilization of p21 (Cip1/WAF1) following Tip60-dependent acetylation is required for p21-mediated DNA damage response

Cell Death Differ. 2013 Apr;20(4):620-9. doi: 10.1038/cdd.2012.159. Epub 2012 Dec 14.

Authors

M-S Lee¹, J Seo, D Y Choi, E-W Lee, A Ko, N-C Ha, J Bok Yoon, H-W Lee, K Pyo Kim, J Song

Affiliation

¹ Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.

Abstract

The molecular mechanisms controlling post-translational modifications of p21 have been pursued assiduously in recent years. Here, utilizing mass-spectrometry analysis and site-specific acetyl-p21 antibody, two lysine residues of p21, located at amino-acid sites 161 and 163, were identified as Tip60-mediated acetylation targets for the first time. Detection of adriamycin-induced p21 acetylation, which disappeared after Tip60 depletion with concomitant destabilization of p21 and disruption of G1 arrest, suggested that Tip60-mediated p21 acetylation is necessary for DNA damage-induced cell-cycle regulation. The ability of 2KQ, a mimetic of acetylated p21, to induce cell-cycle arrest and senescence was significantly enhanced in p21 null MEFs compared with those of cells expressing wild-type p21. Together, these observations demonstrate that Tip60-mediated p21 acetylation is a novel and essential regulatory process required for p21-dependent DNA damage-induced cell-cycle arrest.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Amino Acid Motifs
Amino Acid Sequence
Animals
Cell Cycle Checkpoints
Cell Line
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
DNA Damage*
DNA Repair
HCT116 Cells
Histone Acetyltransferases / antagonists & inhibitors
Histone Acetyltransferases / genetics
Histone Acetyltransferases / metabolism*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / pharmacology
Lysine Acetyltransferase 5
Mice
RNA Interference
RNA, Small Interfering / metabolism
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Ubiquitination

Substances

Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
Hydroxamic Acids
RNA, Small Interfering
Tumor Suppressor Protein p53
trichostatin A
Histone Acetyltransferases
KAT5 protein, human
Lysine Acetyltransferase 5
Histone Deacetylases