Investigating the Molecular Mechanism of CHRONO: A Novel Repressor of the Circadian Clock
Physical and Biological Sciences
CHEM 195 A,B
Circadian rhythms are 24-hour cycles that coordinate physiology to the solar day in order to regulate sleep/wake cycles, metabolism, temperature, blood pressure, and circulating hormones. On a molecular level, the CLOCK:BMAL1 complex tunes cellular clocks by binding both activators and repressors. The novel protein CHRONO (computationally highlighted repressor of the network oscillator) recently entered the spotlight as an additional repressor of the circadian clock. I set out to characterize the structure of CHRONO and determine its binding interactions with other proteins. First, I verified that BMAL1 interacts with CHRONO, and investigated the strength and specific location of this interaction. I mapped binding to the transactivation domain (TAD) of BMAL1, a site known to bind other regulators of the clock. I also identified a point mutation that disrupts the tight interaction. These findings provide key insights on CHRONO’s involvement as a negative regulator of the clock and establish a foundation on which to base future biochemical and biophysical studies. In our modern 24/7 society, circadian stress-based disorders such as jet lag, shift work sleep disorder, cancer, and cardiovascular disease, all pose significant threats to public health. Elucidating the complexities of CHRONO’s structure and function allows the fine regulatory tuning of the circadian clock to be better understood and lends insight to the possibility of circadian manipulation and potential pharmacological control.
