A Blog Around The Clock

From June 26, 2006....

In the beginning, there was period.

Before 1995, the only known circadian clock genes were period (Per) in Drosophila melanogaster (wine fly) and frequency (Frq) in Neurospora crassa (bread mold). Some mutations, though not characterized at the molecular level, were also known in Chlamydomonas, Euglena as well as the famous Tau-mutation in hamsters.

I still remember the strained mathematical models attempting to account for a 24-hour rhythm with just a single gene controlling its own expression. We now know that multiple genes are involved in circadian function in invertebrates and vertebrates, many of which are the same across the animal kingdom and even play the same roles within the circadian mechanism.

But back in 1995, the discovery of TIMELESS (tim) by Amita Seghal was a really big deal - here was a protein that binds to Per in the cytoplasm and is degraded by exposure of the animal to light. That was the beginning of the molecular revolution in chronobiology - finally there was a system in which both the freerunning rhythms and entrainment by light could be studied at the level of the molecules.

It is not surprising that Dr.Seghal, among other things, still pursues the study of TIMELESS. Although this gene is not at all involved in the circadian clock in mammals (where the role is taken by cryptochrome, which has its own role in the Drosophila clock), it is one of the key players in the Drosophila system which, in turn, is the key system for every genetic investigation imaginable. In other words, even if the identities of players are different between invertebrates and vertebrates, the logic of the circadian system is likely to be the same.

In the latest paper in Science, Dr.Seghal and collaborators report the identification of a new gene involved in circadian regulation. They named it JETLAG (Jet). In a series of elegant experiments they show that light, by induction of 3D transformation of CRY (cryptochrome protein), induces the phosphorilation of TIMELESS. JET, then, is capable of binding to TIM and helps degrade TIMELESS protein:

Our results, together with those of previous studies, suggest the following model of how light resets the clock in Drosophila. Upon light exposure, CRY undergoes conformational change, allowing it to bind TIM. TIM is then modified by phosphorylation, which allows JET to target TIM for ubiquitination and rapid degradation by the proteasome pathway.