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Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

(J. Biol. Chem., 284(37), 25149-25159, 2009)

In the molecular oscillatory mechanism governing circadian rhythms, CLOCK and BMAL1 transactivate Per and Cry genes through E-box elements, and translated PER and CRY proteins negatively regulate their own transactivation. Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription, but the role of BMAL2 in the circadian clockwork is still elusive. Sasaki et al. in Fukada lab characterized BMAL2 function in NIH3T3 cells, and found that the cellular rhythms are blunted by Bmal2 knockdown as well as Bmal1 knockdown (Fig. 1), indicating that both Bmal1 and Bmal2 are essential for the molecular oscillation. Luciferase reporter assays revealed that CRY2 inhibited the transactivation mediated by BMAL1:CLOCK more strongly than that by BMAL2:CLOCK (Fig. 2A). In contrast, PER2 showed a stronger inhibitory effect on BMAL2:CLOCK than on BMAL1:CLOCK (Fig. 2B). The molecular link between BMAL2 and PER2 was further strengthened by the fact that PER2 exhibited a greater affinity for BMAL2 than for BMAL1 in co-immunoprecipitation experiments. Importantly, the efficiencies of BMAL2:CLOCK-mediated transactivation relative to that achieved by BMAL1:CLOCK were dependent heavily on the E-box-containing sequences present in the promoter regions of clock genes (Fig. 2C). These data strongly suggested distinguishable roles of the two BMALs in the circadian transcription (Fig. 3).