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Unlikely partners? Cell's waste disposal system regulates body clock proteins

Date:
October 6, 2015
Source:
Perelman School of Medicine at the University of Pennsylvania
Summary:
Researchers have a new genome screen that has identified partner molecules of cell-waste disposal proteins. They applied their new method to identify other clock partners that target a multipurpose cell nucleus receptor for disposal.
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Rhythmic expression of key genes is essential for maintaining proper timekeeping of the body's clock. In addition, rhythmic degradation of clockwork proteins is also crucial. However, surprisingly, researchers know little about these specific processes.

A new Penn-led study describes a new genome screen that identified partner molecules of cell-waste disposal proteins. The team led by John Hogenesch, PhD, a professor of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine at University of Pennsylvania and Jason DeBruyne, PhD, a former postdoctoral fellow in the Hogenesch lab and now an assistant professor at Morehouse School of Medicine in Atlanta, applied their new method to identifying other clock partners that target a multipurpose cell nucleus receptor for disposal. Their findings were published online ahead of print in the Proceedings of the National Academy of Sciences.

"Our goal was not really to study clock biology," said senior author Hogenesch. "Rather, our aim was to develop a genome-wide screen to identify key players involved in protein stability and breakdown."

The proteins they were looking for are called ligases. These recognize specific proteins and direct the addition of a molecule onto waste proteins to dispatch the protein to be recycled to the proteosome. This is the cell compartment that breaks up used proteins into its basic amino acids. To validate the screen, the team tagged several of their favorite clock proteins with a short protein tag that's easily recognized by antibodies. The team then used high throughput imaging to see what ligases increase and decrease the levels of their favorite clock proteins in cells. They found that the ligase Fbxl3 was a regulator of Cry proteins, critical components of the core clock. They also found that a protein called Seven in absentia 2 (Siah2) is a key regulator of the turnover of a well-studied, clock nuclear protein called RevErbα on a 24-hour cycle.

Certain ligases, like Fbxl3, can be targeted with small molecules. "These ligases are being actively developed in drug discovery efforts," Hogenesch noted. "Most proteins don't bind with small molecules. With this screen, we may be able to overcome that limitation by finding the ligase that regulates their levels and function. Small molecules against the ligase, then, could indirectly regulate the amount and therefore activity of the 'undruggable' protein."

The researchers hope that by applying this new method, more ligase drug targets can be found and developed into new therapies across the spectrum of health challenges.


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Materials provided by Perelman School of Medicine at the University of Pennsylvania. Note: Content may be edited for style and length.


Journal Reference:

  1. Jason P. DeBruyne, Julie E. Baggs, Trey K. Sato, John B. Hogenesch. Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock. Proceedings of the National Academy of Sciences, 2015; 201501204 DOI: 10.1073/pnas.1501204112

Cite This Page:

Perelman School of Medicine at the University of Pennsylvania. "Unlikely partners? Cell's waste disposal system regulates body clock proteins." ScienceDaily. ScienceDaily, 6 October 2015. <www.sciencedaily.com/releases/2015/10/151006124042.htm>.
Perelman School of Medicine at the University of Pennsylvania. (2015, October 6). Unlikely partners? Cell's waste disposal system regulates body clock proteins. ScienceDaily. Retrieved May 8, 2017 from www.sciencedaily.com/releases/2015/10/151006124042.htm
Perelman School of Medicine at the University of Pennsylvania. "Unlikely partners? Cell's waste disposal system regulates body clock proteins." ScienceDaily. www.sciencedaily.com/releases/2015/10/151006124042.htm (accessed May 8, 2017).