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Nat Struct Mol Biol. 2015 Jun;22(6):476-484. doi: 10.1038/nsmb.3018. Epub 2015 May 11.

Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus.

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Department of Biological Sciences, University of Memphis, Memphis, Tennessee USA.
Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee USA.
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California USA.
Center for Circadian Biology, University of California San Diego, San Diego, California USA.
Contributed equally


The molecular circadian clock in mammals is generated from transcriptional activation by the bHLH-PAS transcription factor CLOCK-BMAL1 and subsequent repression by PERIOD and CRYPTOCHROME (CRY). The mechanism by which CRYs repress CLOCK-BMAL1 to close the negative feedback loop and generate 24-h timing is not known. Here we show that, in mouse fibroblasts, CRY1 competes for binding with coactivators to the intrinsically unstructured C-terminal transactivation domain (TAD) of BMAL1 to establish a functional switch between activation and repression of CLOCK-BMAL1. TAD mutations that alter affinities for co-regulators affect the balance of repression and activation to consequently change the intrinsic circadian period or eliminate cycling altogether. Our results suggest that CRY1 fulfills its role as an essential circadian repressor by sequestering the TAD from coactivators, and they highlight regulation of the BMAL1 TAD as a critical mechanism for establishing circadian timing.

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