title: Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3.
abstract: The key member of the MOZ (monocyticleukaemia zinc finger protein), Ybf2/Sas3, Sas2, and TIP60 acetyltransferases family, Tat-interactive protein, 60 kD (TIP60), tightly modulates a wide array of cellular processes, including chromatin remodeling, gene transcription, apoptosis, DNA repair, and cell cycle arrest. The function of TIP60 can be regulated by SIRT1 through deacetylation. Here we found that TIP60 can also be functionally regulated by HDAC3. We identified six lysine residues as its autoacetylation sites. Mutagenesis of these lysines to arginines completely abolishes the autoacetylation of TIP60. Overexpression of HDAC3 increases TIP60 ubiquitination levels. However, unlike SIRT1, HDAC3 increased the half-life of TIP60. Further study found that HDAC3 colocalized with TIP60 both in the nucleus and the cytoplasm, which could be the reason why HDAC3 can stabilize TIP60. The deacetylation of TIP60 by both SIRT1 and HDAC3 reduces apoptosis induced by DNA damage. Knockdown of HDAC3 in cells increased TIP60 acetylation levels and increased apoptosis after DNA damage. Together, our findings provide a better understanding of TIP60 regulation mechanisms, which is a significant basis for further studies of its cellular functions.
authors.affiliation: From the School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China, the Department of Medical and Research Technology and Department of Pathology, Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Jingjie
authors.initials: J
authors.lastname: Yi
authors.affiliation: the Department of Medical and Research Technology and Department of Pathology, Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland 21201, the Department of Rheumatology, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, China, and.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Huang
authors.affiliation: the Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Yang
authors.affiliation: the Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.affiliation: the Institute for Cancer Genetics and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.affiliation: the Department of Medical and Research Technology and Department of Pathology, Program in Oncology, Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland 21201, the Peking University Health Science Center, Beijing 100191, China, JLuo@som.umaryland.edu.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Luo
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006207:Half-Life; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D000099186:Histone Deacetylase 3
chemical_list: D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D008239:Lysine; D000074443:Lysine Acetyltransferase 5; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D000099186:Histone Deacetylase 3; C098489:KAT5 protein, human; C447939:SIRT1 protein, human
keywords: Apoptosis; DNA Damage; Histone Acetylase; Histone Deacetylase 3 (HDAC3); Ubiquitylation (Ubiquitination)