The G2-to-M transition (or prophase) checkpoint of the cell cycle is a critical regulator of mitotic entry.
SIRT2, a tumor suppressor gene, contributes to the control of this checkpoint by blocking mitotic entry under cellular stress. However, the mechanism underlying both
SIRT2 activation and regulation of the G2-to-M transition remains largely unknown. Here, we report the formation of a multiprotein complex at the G2-to-M transition in vitro and in vivo. Group IVA cytosolic
phospholipase A2 (cPLA2α) acts as a bridge in this complex to promote binding of
SIRT2 to
cyclin A-Cdk2.
Cyclin A-Cdk2 then phosphorylates
SIRT2 at Ser331. This phosphorylation reduces
SIRT2 catalytic activity and its binding affinity to centrosomes and mitotic spindles, promoting G2-to-M transition. We show that the inhibitory effect of cPLA2α on
SIRT2 activity impacts various cellular processes, including cellular levels of
histone H4 acetylated at K16 (Ac-H4K16) and Ac-α-
tubulin. This regulatory effect of cPLA2α on
SIRT2 defines a novel function of cPLA2α independent of its
phospholipase activity and may have implications for the impact of SIRT2-related effects on
tumorigenesis and age-related diseases.