Abstract: A cell autonomous molecular clock produces robust 24-hr rhythms and coordinates physiological processes with the environment. In mammals, the clock is composed of a heterodimeric transcription factor (CLOCK and BMAL1), which drives expression of output components and members of a repressive complex, CRYPTOCHROME (CRY) and PERIOD (PER), which inhibits CLOCK/BMAL1.

There are two CRYS in mammals and loss of both renders the clock completely arrhythmic, while loss of one results in changes in the circadian period:  loss of CRY1 results in clocks that run fast, while loss of CRY2 results in clocks that run slow. 

Vertebrate Cryptochromes have evolved from a family of DNA repair enzymes called 6-4 Photolyases. These enzymes contain two pockets, which bind to a flavin adenine dinucleotide (FAD) and a secondary cofactor (pterin or deazaflavin) respectively, and harvest blue light to reduce UV-damaged DNA.

Vertebrate CRYs no longer function as blue light photoreceptors and the role of the cofactor pockets is mysterious. Additionally, how the two CRY proteins, which are thought to have biochemical function can affect the period in opposite ways is not understood.  

In this seminar, I will present structural, functional and biochemical data that uncover key differences between the two CRY proteins and reveal the roles of the “cofactor pockets” in these mammalian proteins.  Together these findings begin to explain how the CRY proteins can set the correct circadian period in the mammalian cell.

Suggested Readings:
"Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex"
2. "Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length"

Event Contact:
Dr. Shihoko Kojima