title: Stabilization of p21 (Cip1/WAF1) following Tip60-dependent acetylation is required for p21-mediated DNA damage response.
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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: M-S
authors.initials: MS
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Seo
authors.forename: D Y
authors.initials: DY
authors.lastname: Choi
authors.forename: E-W
authors.initials: EW
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Ko
authors.forename: N-C
authors.initials: NC
authors.lastname: Ha
authors.forename: J Bok
authors.initials: JB
authors.lastname: Yoon
authors.forename: H-W
authors.initials: HW
authors.lastname: Lee
authors.forename: K Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Song
mesh_terms: D000107:Acetylation / Q000187:drug effects; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D045325:HCT116 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D006655:Histone Deacetylases