Charles Weitz, MD, PhD

Mammalian Circadian Clocks

Circadian clocks are molecular oscillators with ~24-hour periods that drive daily biological rhythms.  Such clocks are found in all of the major branches of life, and they likely represent ancient timekeeping systems important for predicting daily environmental cycles on our rotating planet.  In mammals, circadian clocks are present in most if not all cells. These distributed clocks control a myriad of processes, in aggregate creating coherent 24-hour programs of physiology and behavior.

A picture of how circadian clocks are built has emerged in the last two decades.  The core mechanism is a transcriptional feedback loop, wherein the protein products of several clock genes build the molecular machinery to inhibit the transcription factor responsible for their own production.  The molecular components of circadian clocks are conserved from insects to humans.

The Weitz lab uses molecular biology, biochemistry, genetics, and structural biology to investigate the mammalian circadian clock.  The focus of our efforts at present is to understand the circadian clock in terms of the integrated functions of its several multi-protein machines.  This effort is principally based on the purification of endogenous circadian clock protein complexes from mouse tissues and their biochemical analysis and structural study by cryo-electron microscopy.

Fig. 1.  Class-average electron microscopy images of the mouse nuclear PER complex, a core circadian clock machine.  It is a 1.9-MDa assembly of about thirty proteins that appears as a quasi-spherical, beaded particle of 40-nm diameter. Our current work provides an initial low-resolution view of the structural organization of endogenous clock machinery from a eukaryote.  We aim to obtain high-resolution structures.

Selected papers: 

Duong HA, Robles MS, Knutti K, Weitz CJ.  A molecular mechanism for circadian clock negative feedback. Science  332, 1436-1439 (2011).

Padmanabhan K, Robles MS, Westerling T, Weitz CJ.  Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science  337, 599-602 (2012).

Kim JY, Kwak PB, Weitz CJ. Specificity in circadian clock feedback from targeted reconstitution of the NuRD co-repressor.  Mol. Cell  56, 738-748 (2014).

Aryal RA, Kwak PB, Tamayo AG, Chiu PL, Walz T, Weitz CJ.  Macromolecular assemblies of the mammalian circadian clock.  Mol. Cell  (2017, in press). 

"The focus of our efforts is to understand the circadian clock in terms of the integrated functions of its several macromolecular protein machines."