Commentary Volume 2, Issue 5 pp 251—254

Figure 2. Core components of the circadian transcriptional clock. Brain- and Muscle ARNT-like protein (BMAL1) heterodimerizes with CLOCK protein to bind E-box motifs in the promoter regions of downstream target genes, such as Period (Per 1,2) and Cryptochrome (Cry1,2) genes. PERIOD proteins (PERs) heterodimerize with CRYPTOCHROME proteins (CRYs) in order to inhibit CLOCK:BMAL1, thus closing an autoregulatory negative-feedback loop. Blocking activity of CLOCK:BMAL1 in Bmal1 knock-out mice disrupts normal circadian rhythms, and increases reactive-oxygen species (ROS), while concomitantly decreasing memory and lifespan. Circadian clock output regulates a variety of biological and physiological processes, including circadian rhythms, metabolism, learning and memory, ROS/reactive nitrogen species (RNS) homeostasis, aging and longevity, and the cell cycle.