The ATAC acetyl transferase complex controls mitotic progression by targeting non-histone substrates

• Published in: The EMBO journal Vol. 29; no. 14; pp. 2381 - 2394
• Main Authors: Orpinell, Meritxell, Fournier, Marjorie, Riss, Anne, Nagy, Zita, Krebs, Arnaud R, Frontini, Mattia, Tora, Làszlò
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 21.07.2010; Nature Publishing Group UK; Blackwell Publishing Ltd; EMBO Press; Nature Publishing Group
• Subjects: Acetyltransferases - genetics; Acetyltransferases - metabolism; Ada; Amino Acid Sequence; Animals; Cell cycle; Chromatin; Compaction; Cyclin A - metabolism; Cyclin-Dependent Kinase 2 - metabolism; Deoxyribonucleic acid; DNA; EMBO06; EMBO09; Gene expression; HeLa Cells; histone; Humans; Life Sciences; Mice; Mitosis - physiology; Molecular biology; Molecular Sequence Data; NIH 3T3 Cells; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Proteins; RNA Interference; spindle; Spindle Apparatus - metabolism; Tubulin - metabolism; α-tubulin; histone; chromatin; α‐tubulin; spindle; Ada
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2010.125

All DNA‐related processes rely on the degree of chromatin compaction. The highest level of chromatin condensation accompanies transition to mitosis, central for cell cycle progression. Covalent modifications of histones, mainly deacetylation, have been implicated in this transition, which also involves transcriptional repression. Here, we show that the Gcn5‐containing histone acetyl transferase complex, A da T wo A c ontaining (ATAC), controls mitotic progression through the regulation of the activity of non‐histone targets. RNAi for the ATAC subunits Ada2a/Ada3 results in delayed M/G1 transition and pronounced cell division defects such as centrosome multiplication, defective spindle and midbody formation, generation of binucleated cells and hyperacetylation of histone H4K16 and α‐tubulin. We show that ATAC localizes to the mitotic spindle and controls cell cycle progression through direct acetylation of Cyclin A/Cdk2. Our data describes a new pathway in which the ATAC complex controls Cyclin A/Cdk2 mitotic function: ATAC/Gcn5‐mediated acetylation targets Cyclin A for degradation, which in turn regulates the SIRT2 deacetylase activity. Thus, we have uncovered an essential function for ATAC in regulating Cyclin A activity and consequent mitotic progression.