The ATAC acetyl transferase complex controls mitotic progression by targeting non-histone substrates.
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, Ada Two A containing (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 alpha-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.
Orpinell
Meritxell
M
Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U964, Université de Strasbourg, Illkirch Cedex, France.
Fournier
Marjorie
M
Riss
Anne
A
Nagy
Zita
Z
Krebs
Arnaud R
AR
Frontini
Mattia
M
Tora
Làszlò
L
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D014404:Tubulin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor