title: Degradation of cyclin A is regulated by acetylation.
abstract: Cyclin A accumulates at the onset of S phase, remains high during G(2) and early mitosis and is degraded at prometaphase. Here, we report that the acetyltransferase P/CAF directly interacts with cyclin A that as a consequence becomes acetylated at lysines 54, 68, 95 and 112. Maximal acetylation occurs simultaneously to ubiquitylation at mitosis, indicating importance of acetylation on cyclin A stability. This was further confirmed by the observation that the pseudoacetylated cyclin A mutant can be ubiquitylated whereas the nonacetylatable mutant cannot. The nonacetylatable mutant is more stable than cyclin A WT (cycA WT) and arrests cell cycle at mitosis. Moreover, in cells treated with histone deacetylase inhibitors cyclin A acetylation increases and its stability decreases, thus supporting the function of acetylation on cyclin A degradation. Although the nonacetylatable mutant cannot be ubiquitylated, it interacts with the proteins needed for its degradation (cdks, Cks, Cdc20, Cdh1 and APC/C). In fact, its association with cdks is increased and its complexes with these kinases display higher activity than control cycA WT-cdk complexes. All these results indicate that cyclin A acetylation at specific lysines is crucial for cyclin A stability and also has a function in the regulation of cycA-cdk activity.
authors.affiliation: Faculty of Medicine, Department of Cell Biology and Pathology, University of Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Mateo
authors.forename: M
authors.initials: M
authors.lastname: Vidal-Laliena
authors.forename: N
authors.initials: N
authors.lastname: Canela
authors.forename: L
authors.initials: L
authors.lastname: Busino
authors.forename: M A
authors.initials: MA
authors.lastname: Martinez-Balbas
authors.forename: M
authors.initials: M
authors.lastname: Pagano
authors.forename: N
authors.initials: N
authors.lastname: Agell
authors.forename: O
authors.initials: O
authors.lastname: Bachs
mesh_terms: D000107:Acetylation; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor