Role of the CLOCK Protein in the Mammalian Circadian Mechanism

TLDR

The mouse Clock gene encodes a bHLH‑PAS protein that regulates circadian rhythms by forming heterodimeric transcription factors. Potential CLOCK partners were identified via a two‑hybrid screen, and BMAL1 was shown to co‑express with CLOCK and PER1 at circadian clock sites in brain and retina. CLOCK‑BMAL1 heterodimers activate transcription from E‑box elements adjacent to per1, whereas mutant CLOCK‑BMAL1 complexes bind DNA but fail to activate, indicating that CLOCK‑BMAL1 drives the positive arm of per transcriptional oscillations that underlie circadian rhythmicity.

Abstract

The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor–binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.