Joanna Chiu Leads Groundbreaking Research on Circadian Rhythms; Published in Journal Cell
April 26, 2011
Molecular geneticist Joanna Chiu is the lead author on a newly published paper in the journal Cell. (Photo by Kathy Keatley Garvey)
DAVIS--Molecular geneticist Joanna Chiu of the UC Davis Department of Entomology and colleagues from Rutgers University, the State University of New Jersey, have identified a new mechanism that slows down or speeds up the internal clock of fruit flies, research that could help lead the way to alleviate human sleep disorders.
By mutating one amino acid in a single protein, “we changed the speed of the internal clock and flies now ‘think’ it is 16 hours a day instead of 24 hours a day,” said Chiu, an assistant professor of entomology. “Our goal, of course, is not to trick flies into thinking the day is shorter or longer, but to dissect this complex phospho-circuit (phosphorylation sites) that controls clock speed in metazoans.”
Their work, involving the fruit fly, Drosophila melanogaster, and funded by the National Institutes of Health, is published in the current edition of the journal Cell.
In previous studies, they identified at least 30 phosphorylation sites on a fly protein, PERIOD. These PERIOD proteins, involved in the regulation of circadian rhythms, exist in all insects and in mammals.
“We know that besides affecting degradation rate, phosphorylation of PERIOD proteins also affects its subcellular localization and transcriptional repressor function,” Chiu said.
The researchers also discovered that NEMO, a protein kinase, is involved in animal clockworks, a protein never linked before to the regulation of circadian rhythms.
Chiu, a former postdoctoral fellow in the laboratory of professor Issac Edery of the Department of Molecular Biology and Biochemistry and Center for Advanced Biotechnology and Medicine, Rutgers, is the lead author of the paper. Edery and Hyuk Wan Ko, a former graduate student at Rutgers and now an assistant professor at the Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, South Korea, co-authored the paper.
Specifically, they identified a cluster of PERIOD phosphorylation sites including serine 596, whose function is to delay the phosphorylation of serine 47, an event that promotes PERIOD degradation. Phosphorylation of serine 596 therefore indirectly slows down the degradation rate of PERIOD. This is the first phospho-delay circuitry ever identified in organismal clocks.
Abnormal PERIOD phosphorylation has been linked to human sleep disorders. “The knowledge gained from these studies could potentially be used to develop strategies for correcting disorders associated with phosphorylation defects in human circadian clocks,” Chiu said.
The world of circadian clocks is a complex one. “Living organisms—plants, animals and even bacteria—have an internal clock or timer that helps them to determine the time of day,” Chiu said. “This internal clock is vital to their survival since it allows them to synchronize their activity to the natural environment, so that they can perform necessary tasks at biologically advantageous times of day.”
“A functional clock is required to generate proper circadian rhythms of physiology and behavior including the sleep-wake cycle, daily hormonal variations and mating rhythms,” Chiu said.
“Based on genetics, molecular biology and biochemical experiments performed in many different model organisms, we know that the speed of the internal clock is controlled by a core set of circadian proteins,” Chiu explained. “In insects as well as in mammals, the daily changes in PERIOD protein levels represent a key variable in determining clock speed. De novo synthesis of PERIOD begins around mid-morning. Levels of PERIOD proteins continue to build up throughout the day and into the night, until they are ‘tagged’ for degradation in the early morning hours. This biochemical cycle of the PERIOD proteins intelligently corresponds to duration of a day.”
If for any reason the timing of the biochemical cycle of PERIOD is altered, “the speed of our internal clock will be different,” she said.
Previously, as a postdoctoral fellow in the Edery laboratory, Chiu showed that in fruit flies, the timing of PERIOD degradation is highly sensitive to its phosphorylation state. “Phosphate groups carry negative charges, and when they are added onto proteins, they very often change their protein properties,” Chiu explained. “We showed that when PERIOD is phosphorylated at amino acid number 47, a serine residue, it is ‘tagged’ for degradation, signaling the end of the PERIOD biochemical cycle.”
Chiu, who specializes in molecular genetics of animal behavior, joined the UC Davis Department of Entomology faculty in June 2010. She received her doctorate in molecular genetics from the Department of Biology at New York University.
--Kathy Keatley Garvey
UC Davis Department of Entomology