The small G protein RAS2 is involved in the metabolic compensation of the circadian clock in the circadian model .

Accumulating evidence from both experimental and clinical investigations indicates a tight interaction between metabolism and circadian timekeeping; however, knowledge of the underlying mechanism is still incomplete. Metabolic compensation allows circadian oscillators to run with a constant speed at different substrate levels and, therefore, is a substantial criterion of a robust rhythm in a changing environment. Because previous data have suggested a central role of RAS2-mediated signaling in the adaptation of yeast to different nutritional environments, we examined the involvement of RAS2 in the metabolic regulation of the clock in the circadian model organism We show that, in a -deficient strain, the period is longer than in the control. Moreover, unlike in the WT, in Δ, operation of the circadian clock was affected by glucose; compared with starvation conditions, the period was longer and the oscillation of expression of the () gene was dampened. In constant darkness, the delayed phosphorylation of the FRQ protein and the long-lasting accumulation of FRQ in the nucleus were in accordance with the longer period and the less robust rhythm in the mutant. Although glucose did not affect the subcellular distribution of FRQ in the WT, highly elevated FRQ levels were detected in the nucleus in Δ RAS2 interacted with the RAS-binding domain of the adenylate cyclase , and the cAMP analogue 8-bromo-cyclic AMP partially rescued the circadian phenotype We therefore propose that RAS2 acts via a cAMP-dependent pathway and exerts significant metabolic control on the circadian clock.