The circadian clock is driven by cell-autonomous transcription/translation 
feedback loops. The BMAL1 transcription factor is an indispensable component of 
the positive arm of this molecular oscillator in mammals. Here, we present a 
molecular genetic screening assay for mutant circadian clock proteins that is 
based on real-time circadian rhythm monitoring in cultured fibroblasts. By using 
this assay, we identified a domain in the extreme C terminus of BMAL1 that plays 
an essential role in the rhythmic control of E-box-mediated circadian 
transcription. Remarkably, the last 43 aa of BMAL1 are required for 
transcriptional activation, as well as for association with the circadian 
transcriptional repressor CRYPTOCHROME 1 (CRY1), depending on the coexistence of 
CLOCK protein. C-terminally truncated BMAL1 mutant proteins still associate with 
mPER2 (another protein of the negative feedback loop), suggesting that an 
additional repression mechanism may converge on the N terminus. Taken together, 
these results suggest that the C-terminal region of BMAL1 is involved in 
determining the balance between circadian transcriptional activation and 
suppression.