Degradation of cyclin A is regulated by acetylation

Abstract

Cyclin A accumulates at the onset of S phase, rem ains high during G2 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, Cdc 20, Cdh1 and APC/C). In fact, it s 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.

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Previous reports have shown that acetylation of nonhistone proteins may be linked to regulation of their stability (Hernandez-Hernandez et al, 2006;Leduc et al, 2006;Mateo et al, 2009 (Figure 2c). This observation implies that N3 IC is a substrate of HAT-dependent acetylation.…”

Histone Deacetylase 3 Regulates Cyclin A Stability

“…Plasmids-HA-cyclin A, Flag-cyclin A-WT, Flag-cyclin A-4R, and GST-cyclin A-WT were described elsewhere (26). GST-cyclin A 1-171, and GST-cyclin A 171-432 were described elsewhere (31).…”

“…We previously reported that, at mitosis, cyclin A is acetylated by the acetyltransferase PCAF at specific lysine residues: K54, K68, K95, and K112 (26). These lysines are located on the N-terminal domain of cyclin A and specifically at domains implicated in the regulation of the stability of the protein (23,27).…”

High resolution live cell imaging reveals novel cyclin A2 degradation foci involving autophagy

“…Cyclin A2 is ubiquitylated by the anaphasepromoting complex (also called the 'cyclosome', APC/C), which is activated by cell-division cycle protein 20 (Cdc20). The degradation of cyclin A2 is also regulated by acetylation (Mateo et al, 2009). Cyclin A2 proteolysis is required for chromosome alignment and anaphase progression (den Elzen and Pines, 2001).…”